Substituted quinoline derivatives as h1 receptor antagonists

ABSTRACT

The present invention relates to compounds of formula (I), 
     
       
         
         
             
             
         
       
     
     and salts thereof, processes for their preparation, to compositions containing them and to their use in the treatment of various diseases, such as allergic rhinitis.

The present invention relates to a class of compounds which arequinolinyloxypiperidine and pyrrolidine derivatives, processes for theirpreparation, pharmaceutical compositions containing them and to theiruse in the treatment of various diseases, in particular inflammatoryand/or allergic diseases of the respiratory tract.

Allergic rhinitis (seasonal and perennial), pulmonary inflammation andcongestion are medical conditions that are often associated with otherconditions such as asthma and chronic obstructive pulmonary disease(COPD). In general, these conditions are mediated, at least in part, byinflammation associated with the release of histamine from variouscells, in particular mast cells.

Allergic rhinitis, also known as ‘hay fever’ affects a large proportionof the population worldwide. There are two types of allergic rhinitis,seasonal and perennial. The clinical symptoms of seasonal allergicrhinitis typically include nasal itching and irritation, sneezing andwatery rhinorrhea, which is often accompanied by nasal congestion. Theclinical symptoms of perennial allergic rhinitis are similar, exceptthat nasal blockage may be more pronounced. Either type of allergicrhinitis may also cause other symptoms, such as itching of the throatand/or eyes, epiphora and oedema around the eyes. The symptoms ofallergic rhinitis may vary in intensity from the nuisance level todebilitating.

Allergic rhinitis and other allergic conditions are associated with therelease of histamine from various cell types, but particularly mastcells. The physiological effects of histamine are classically mediatedby three receptor subtypes, termed H1, H2 and H3. H1 receptors arewidely distributed throughout the CNS and periphery, and are involved inwakefulness and acute inflammation. H2 receptors mediate gastric acidsecretion in response to histamine. H3 receptors are present on thenerve endings in both the CNS and periphery and mediate inhibition ofneurotransmitter release [Hill et al., Pharmacol. Rev., 49:253-278,(1997)]. A fourth member of the histamine receptor family has beenidentified, termed the H4 receptor [Hough, Mol. Pharmacol., 59:415-419,(2001)]. Whilst the distribution of the H4 receptor appears to berestricted to cells of the immune and inflammatory systems, aphysiological role for this receptor remains to be identified.

The activation of H1 receptors in blood vessels and nerve endings areresponsible for many of the symptoms of allergic rhinitis, which includeitching, sneezing, and the production of watery rhinorrhea. Oralantihistamine compounds which are selective H1 receptor antagonists,such as chlorphenyramine, cetirizine, desloratidine and fexofenadine areeffective in treating the itching, sneezing and rhinorrhea associatedwith allergic rhinitis. Intranasal antihistamines which are selective H1receptor antagonists, such azelastine and levocabastine, are thought tohave similar therapeutic effects to their oral counterparts. However,such compounds generally require twice daily administration and maystill cause sedatation despite their local application.

A class of compounds have been identified as H1 receptor antagonists.

Thus the present invention provides a compound of formula (I)

whereinR¹ represents straight chain C₁₋₆alkyl;a represents 1 or 2;R² represents —C₁₋₆alkylene-R³-R⁴, in which the alkylene is straightchain and is optionally substituted by one C₁₋₃alkyl group, or R²represents a saturated 5 to 7 membered ring containing one SO₂ group;R³ represents —SO₂—, —N(R⁵)SO₂—, —SO₂N(R⁶)— or —N(R⁷)C(O)N(R⁸)—;R⁴ represents —C₁ alkyl, —C₅₋₇cycloalkyl optionally substituted by oneor two C₁₋₃alkyl groups, —C₁₋₃alkyleneC₅₋₇cycloalkyl in which theC₅₋₇cycloalkyl is optionally substituted by one or two C₁₋₃alkyl groups,-aryl optionally substituted by one or two substituents independentlyselected from halogen, C₁₋₃alkyl, trifluoromethyl, or cyano groups, or—C₁₋₃alkylene-aryl optionally substituted by one or two substituentsindependently selected from halogen, C₁₋₃alkyl, trifluoromethyl, orcyano groups;

R⁵, R⁶, R⁷ and R⁸ each independently represent hydrogen or C₁₋₆alkyl;

or together R⁶ and R⁴ represent a saturated 5 to 7 membered ring,optionally containing one —O—, —S—, —NH—, or —N(CH₃)— group;or together R⁸ and R⁴ represent a saturated 5 to 7 membered ring,optionally containing one —O—, —S—, —NH—, or —N(CH₃)— group;or a salt thereof.

The compounds of the invention may be expected to be useful in thetreatment of various diseases in particular inflammatory and/or allergicdiseases, such as inflammatory and/or allergic diseases of therespiratory tract (for example allergic rhinitis) that are associatedwith the release of histamine from cells such as mast cells. Further,preferred compounds show an improved profile, in that they possess oneor more of the following properties:

(i) greater selectivity over the H3 receptor;(ii) lower CNS penetration;(iii) prolonged duration of action;(iv) lower bioavailability/oral absorption.

Compounds having such a profile may be particularly suitable forintranasal delivery, and/or capable of once daily administration and/orfurther may have an improved side effect profile compared with otherexisting therapies.

By ‘selectivity’ it is meant that the compounds may be more potent atthe H1 receptor than at other receptors, particularly the H3 receptorand/or the hERG receptor. The activity at the H1 receptor may be atleast about 10 fold greater (e.g. about 100 fold greater) than activityat the H3 receptor.

In one embodiment, R⁴ represents —C₁₋₆alkyl, —C₅₋₇cycloalkyl optionallysubstituted by one or two C₁₋₃alkyl groups, —C₁₋₃alkyleneC₅₋₇cycloalkylin which the C₅₋₇cycloalkyl is optionally substituted by one or twoC₁₋₃alkyl groups, -aryl optionally substituted by one or twosubstituents independently selected from halogen, C₁₋₃alkyl,trifluoromethyl, or cyano groups, or —C₁₋₃alkylene-aryl optionallysubstituted on aryl by one or two substituents independently selectedfrom halogen, C₁₋₃alkyl, trifluoromethyl, or cyano groups.

In one embodiment, R¹ represents straight chain C₁₋₆alkyl;

a represents 1 or 2;R² represents —C₁₋₆alkylene-R³-R⁴, in which the alkylene is straightchain and is optionally substituted by one C₁₋₃alkyl group, or R²represents a saturated 5 to 7 membered ring containing one SO₂ group;R³ represents —SO₂—, —N(R⁵)SO₂, —SO₂N(R⁶)— or —N(R⁷)C(O)N(R⁸)—;R⁴ represents —C₁₋₆alkyl, —C₅₋₇cycloalkyl optionally substituted by oneor two C₁₋₃alkyl groups, —C₁₋₃alkyleneC₅₋₇cycloalkyl in which theC₅₋₇cycloalkyl is optionally substituted by one or two C₁₋₃alkyl groups,-aryl optionally substituted by one or two substituents independentlyselected from halogen, C₁₋₃alkyl, trifluoromethyl, or cyano groups, or—C₁₋₃alkylene-aryl optionally substituted by one or two substituentsindependently selected from halogen, C₁₋₃alkyl, trifluoromethyl, orcyano groups;R⁵, R⁶, R⁷ and R⁸ each independently represent hydrogen or C₁₋₆alkyl;or a salt thereof.

In another embodiment, R¹ represents C₂₋₅alkyl;

a represents 1 or 2;R² represents —C₂₋₅alkylene-R³-R⁴, in which the alkylene is straightchain and is optionally substituted by one C₁₋₃alkyl (e.g. methyl)group, or R² represents a saturated 5 membered ring containing one SO₂group;R³ represents —SO₂—, —N(R⁵)SO₂, —SO₂N(R⁶)— or —N(R⁷)C(O)N(R⁸)—;R⁴ represents —C₁₋₄alkyl, —C₅₋₆cycloalkyl, —C₁alkyleneC₅₋₆cycloalkyl,-aryl (e.g. phenyl) optionally substituted by one or two (e.g. one)substituent(s) independently selected from halogen, C₁₋₃alkyl (e.g.methyl), trifluoromethyl, or cyano groups, or —C₁alkylene-aryl (e.g.methylphenyl) optionally substituted by one or two (e.g. one)substituent(s) independently selected from halogen, C₁₋₃alkyl (e.g.methyl), trifluoromethyl, or cyano groups;R⁵, R⁶, R⁷ and R⁸ each independently represent hydrogen or C₁₋₃alkyl;or a salt thereof.

In another embodiment R¹ represents C₂₋₅alkyl (e.g. n-butyl orn-pentyl).

In another embodiment, a represents 2.

In another embodiment, R² represents —C₂₋₃alkylene-R³-R⁴, in which thealkylene is straight chain and is optionally substituted by oneC₁₋₃alkyl (e.g. methyl) group, or R² represents a saturated fivemembered ring containing one SO₂ group.

In another embodiment, R² represents —C₂₋₅alkylene-R³-R⁴ (e.g.—C₂₋₄alkylene-R³-R⁴), in which the alkylene is straight chain and isoptionally substituted by one C₁₋₃alkyl (e.g. methyl) group.

In another embodiment, R³ represents —SO₂—, —N(R⁵)SO₂— or —SO₂N(R⁶)—.

In another embodiment, R³ represents —N(R⁵)SO₂— or —SO₂N(R⁶)—.

In another embodiment, R³ represents —SO₂—.

In another embodiment, R³ represents —N(R⁵)SO₂—.

In another embodiment, R³ represents —SO₂N(R⁶)—.

In another embodiment, R⁴ represents —C₁₋₆alkyl, —C₅₋₇cycloalkyl,—C₁₋₃alkyleneC₅₋₇cycloalkyl, -aryl (e.g. phenyl) optionally substitutedby one or two (e.g. one) substituent(s) independently selected fromhalogen, C₁₋₃alkyl (e.g. methyl), trifluoromethyl, or cyano groups, or—C₁₋₃alkylene-aryl (e.g. C₁₋₃alkylene-phenyl) optionally substituted byone or two (e.g. one) substituent(s) independently selected fromhalogen, C₁₋₃alkyl (e.g. methyl), trifluoromethyl, or cyano groups.

In another embodiment, R⁴ represents —C₁₋₄alkyl, —C₅₋₆cycloalkyl,—C₁alkyleneC₅₋₆-cycloalkyl, -aryl (e.g. phenyl) optionally substitutedby one or two (e.g. one) substituent(s) independently selected fromhalogen, C₁₋₃alkyl (e.g. methyl), trifluoromethyl, or cyano groups, or—C₁alkylene-aryl (e.g. methylphenyl) optionally substituted by one ortwo (e.g. one) substituent(s) independently selected from halogen,C₁₋₃alkyl (e.g. methyl), trifluoromethyl, or cyano groups.

In another embodiment, R⁴ represents —C₁₋₄alkyl, —C₅₋₆cycloalkyl,—C₁alkyleneC₅₋₆cycloalkyl or -aryl (e.g. phenyl) optionally substitutedby one or two (e.g. one) substituent(s) independently selected fromhalogen, C₁₋₃alkyl (e.g. methyl), trifluoromethyl, or cyano groups.

In another embodiment, R⁴ represents —C₁₋₄alkyl, —C₅₋₆cycloalkyl,—C₁alkyleneC₅₋₆cycloalkyl or unsubstituted aryl (e.g. phenyl).

In another embodiment, R⁵, R⁶, R⁷ and R⁸ each independently representhydrogen or C₁₋₃alkyl (e.g. methyl).

In another embodiment, when R³ represents —SO₂—, R⁴ represents—C₁₋₆alkyl (e.g. methyl, ethyl, propyl, iso-propyl, butyl, ortert-butyl) or C₅₋₇cycloalkyl (e.g. cyclopentyl).

In another embodiment, when R³ represents —N(R⁵)SO₂—, R⁴ represents—C₁₋₆alkyl (e.g. methyl, ethyl, propyl, iso-propyl or iso-butyl),—C₅₋₇cycloalkyl (e.g. cyclohexyl), —C₁₋₃alkyleneC₅₋₇cycloalkyl (e.g.methylcyclohexyl) or unsubstituted aryl (e.g. phenyl) and R⁵ representshydrogen or C₁₋₃alkyl (e.g. methyl).

In another embodiment, when R³ represents —SO₂N(R⁶)—, R⁴ represents—C₁₋₆alkyl (e.g. propyl or tert-butyl) and R⁶ represents hydrogen.

In another embodiment, when R³ represents —N(R⁷)C(O)N(R⁸)—, R⁴represents —C₁ alkyl (e.g. propyl) and R⁷ and R⁸ both representhydrogen.

In another embodiment, there is provided a compound which is6-butyl-8-({1-[3-(ethylsulfonyl)propyl]-4-piperidinyl]oxy}quinoline, ora salt thereof, such as a pharmaceutically acceptable salt thereof.

In another embodiment, there is provided a compound which isN-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide,or a salt thereof, such as a pharmaceutically acceptable salt thereof.

In another embodiment, there is provided a compound which isN-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide,in the form of the free base.

In another embodiment, there is provided a compound which isN-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide,in the form of a dihydrochloride salt.

In another embodiment, there is provided a compound which isN-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide,dihydrochloride salt, polymorphic form 1.

In another embodiment, there is provided a compound of formula (I) asdefined above with the proviso that the compound is not6-butyl-8-({1-[3-(ethylsulfonyl)propyl]-4-piperidinyl}oxy)quinoline, ora salt thereof, such as a pharmaceutically acceptable salt thereof.

In another embodiment, there is provided a compound of formula (I) asdefined above with the proviso that the compound is notN-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide,or a salt thereof, such as a pharmaceutically acceptable salt thereof.

In another embodiment, there is provided a compound of formula (I) asdefined above with the proviso that the compound is not6-butyl-8-({1-[3-(ethylsulfonyl)propyl]-4-piperidinyl}oxy)quinoline orN-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide, or salts thereof, such as pharmaceutically acceptable saltsthereof.

Representative compounds of formula (I) include the compounds ofExamples 1 to 36 and individual isomers thereof, in the form of a freebase, or as salts thereof, such as pharmaceutically acceptable saltsthereof.

It is to be understood that the invention includes all possiblecombinations of groups and substituents described herein.

C₁₋₆alkyl, whether alone or as part of another group, and unlessotherwise stated, may be straight chain or branched. C₁₋₃alkyl shall beinterpreted similarly. Representative examples include, but are notlimited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl,iso-butyl, t-butyl, n-pentyl, neo-pentyl and n-hexyl.

C₁₋₆alkylene, unless otherwise stated, may be straight chain orbranched. C₁₋₃alkylene shall be interpreted similarly. Representativeexamples of straight chain C₁₋₆alkylene include methlyene [—(CH₂)—],ethylene [—(CH₂)₂—], propylene, [—(CH₂)₃—], butylene [—(CH₂)₄—],pentylene [—(CH₂)₅—] and hexylene

As defined herein, the term “aryl” includes single and fused aromaticrings. Representative examples of aryl groups include, but are notlimited to phenyl, indenyl, anthrancenyl and naphthyl. Aryl is intendedto denote all isomers thereof (i.e. all possible points of attachment tothe aryl ring). A representative aryl group is phenyl.

As defined herein, the term “C₅₋₇cycloalkyl” refers to a non-aromaticcyclic hydrocarbon ring having from five to seven carbon atoms. Examplesof such ring systems include cyclopentyl, cyclohexyl and cycloheptyl.

The term “halogen” is used herein to describe, unless otherwise stated,a group selected from fluorine, chlorine, bromine or iodine,particularly fluorine and chlorine.

It is to be understood that the present invention covers compounds offormula (I) as the free base and as salts thereof, for example as apharmaceutically acceptable salt.

It is to be further understood that references hereinafter to compoundsof the invention or to compounds of formula (I) mean a compound offormula (I) as the free base, or as a salt.

The compounds of formula (I) may be in the form of and/or may beadministered as a pharmaceutically acceptable salt. For a review onsuitable salts see Berge et al., J. Pharm. Sci., 1977, 66, 1-19.Suitable pharmaceutically acceptable salts include acid addition salts.As used herein, the term “pharmaceutically acceptable salt”, means anypharmaceutically acceptable salt of a compound of formula (I), whichupon administration to the recipient is capable of providing (directlyor indirectly) a compound of formula (I), or an active metabolite orresidue thereof.

Typically, a pharmaceutically acceptable salt may be readily prepared byusing a desired acid as appropriate. The salt may precipitate fromsolution and be collected by filtration or may be recovered byevaporation of the solvent.

A pharmaceutically acceptable acid addition salt can be formed byreaction of a compound of formula (I) with a suitable inorganic ororganic acid (such as hydrobromic, hydrochloric, sulphuric, nitric,phosphoric, succinic, maleic, formic, acetic, propionic, fumaric,citric, tartaric, lactic, benzoic, salicylic, glutamic, aspartic,p-toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic,naphthalenesulfonic (e.g. 2-naphthalenesulfonic), naphthalene disulfonic(e.g. 1,5-naphthalene disulfonic), naphthoic, 1-hydroxy-2-naphthoic,biphenylsulfonic, xinfanoic or hexanoic acid), optionally in a suitablesolvent such as an organic solvent, to give the salt which is usuallyisolated for example by crystallisation and filtration. Apharmaceutically acceptable acid addition salt of a compound of formula(I) can comprise or be for example a hydrobromide, hydrochloride,sulfate, nitrate, phosphate, succinate, maleate, formate, acetate,propionate, fumarate, citrate, tartrate, lactate, benzoate, salicylate,glutamate, aspartate, p-toluenesulfonate, benzenesulfonate,methanesulfonate, ethanesulfonate, naphthalenesulfonate (e.g.2-naphthalenesulfonate), naphthalene disulfonate (e.g. 1,5-naphthalenedisulfonate), naphthoate, 1-hydroxy-2-naphthoate, biphenylsulfonate,xinfanoate or hexanoate salt. Particular salts are the hydrochloridesalt or dihydrochloride salt of compounds of formula (I).

Compounds of formula (I) in which R³ represents —NR⁵SO₂— or —SO₂NR⁶— mayform base addition salts. Suitable pharmaceutically acceptable basesalts include ammonium salts, alkali metal salts such as those of sodiumand potassium, alkaline earth metal salts such as those of calcium andmagnesium, and salts with organic bases whose pK_(a) is >13.

Other non-pharmaceutically acceptable salts, e.g. oxalates ortrifluoroacetates, may be used, for example in the isolation of thecompounds of formula (I), and are included within the scope of thisinvention.

Particular salts ofN-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamideinclude naphthalene disulfonate salts, such as a 2,6- or a1,5-naphthalene disulfonate salt, e.g. a 1,5-naphthalene disulfonatesalt. Another particular salt is the dihydrochloride salt.

The invention includes within its scope all possible stoichiometric andnon-stoichiometric forms of the salts of the compounds of formula (I).

It will be appreciated that many organic compounds can form complexeswith solvents in which they are reacted or from which they areprecipitated or crystallized. These complexes are known as “solvates”.For example, a complex with water is known as a “hydrate”. Solvents withhigh boiling points and/or solvents which are capable of forminghydrogen bonds such as water, xylene, N-methylpyrrolidinone, methanoland ethanol may be used to form solvates. Methods for identification ofsolvates include, but are not limited to, NMR and microanalysis.Solvates of the compounds of formula (I) are within the scope of theinvention.

The compounds of formula (I) may be in a crystalline or amorphous state,which are included in the scope of the present invention. Furthermore,if crystalline, the compounds of formula (I) may exist in one or morepolymorphic forms, which are included in the scope of the presentinvention. The most thermodynamically stable polymorphic form, at roomtemperature, of compounds of formula (I) is of particular interest.

Polymorphic forms of compounds of formula (I) may be characterized anddifferentiated using a number of conventional analytical techniques,including, but not limited to, X-ray powder diffraction (XRPD), infraredspectroscopy (IR), Raman spectroscopy, differential scanning calorimetry(DSC), thermogravimetric analysis (TGA) and solid state nuclear magneticresonance (ssNMR).

It will be appreciated that the compounds of formula (I) may possess oneor more asymmetric carbon atoms so that optical isomers e.g. enantiomersor diastereoisomers may be formed. The present invention encompassesoptical isomers of the compounds of formula (I) whether as individualisomers isolated such as to be substantially free of the other isomer(i.e. pure) or as mixtures thereof (e.g. racemates and racemicmixtures). An individual isomer isolated such as to be substantiallyfree of the other isomer (i.e. pure) may be isolated such that less thanabout 10%, particularly less than about 1%, for example less than about0.1% of the other isomer is present.

Further, it will be appreciated that the R and S enantiomers may beisolated from the racemate by conventional resolution methods such aspreparative HPLC involving a chiral stationary phase, by resolutionusing fractional crystallisation of a salt of the free base with achiral acid, by chemical conversion to a diastereoisomer using a chiralauxiliary followed by chromatographic separation of the isomers and thenremoval of the chiral auxiliary and regeneration of the pure enantiomer,or by asymmetric synthesis.

Certain compounds of formula (I) may exist in one of several tautomericforms. It will be understood that the present invention encompassestautomers of the compounds of formula (I) whether as individualtautomers or as mixtures thereof.

It will be appreciated from the foregoing that included within the scopeof the invention are solvates, hydrates, optical isomers, tautomers andpolymorphic forms of the compounds of formula (I) and salts thereof.

There is also provided processes for the preparation of compounds offormula (I) or salts thereof.

For the avoidance of doubt, throughout the process section, unlessotherwise stated, (CH₂)_(n) corresponds to the C₁₋₆alkylene defined inR² in the compounds of formula (I), and thus may be optionallysubstituted by one C₁₋₃alkyl group.

According to a first process, A, a compound of formula (I) in which R³represents —SO₂— may be prepared by reacting a compound of formula (II)

with a compound of formula (III)

wherein R¹, a and R⁴ are as defined hereinabove, n represents 1 to 6,(CH₂)_(n) may be optionally substituted by one C₁₋₃alkyl group, and Xrepresents a suitable leaving group such as chlorine, bromine, tosylateor mesylate.

The reaction may typically be carried out in a suitable solvent, such asN,N′-dimethylformamide (DMF), optionally using an appropriate activatingagent, e.g. sodium iodide, with a suitable base, such as sodiumbicarbonate (sodium hydrogen carbonate) or potassium carbonate. Thereaction is typically heated, for example using a microwave oven at atemperature of about 100 to 150° C. for an appropriate time, such asabout 15 to 30 min. Alternatively, the reaction may be heated usingconventional methods for longer periods of time, such as for severalhours or overnight, as appropriate.

Compounds of formula (II) may be prepared according to Scheme 1 below.

Compounds of formula (III) in which X represents chlorine or bromine maybe prepared according to Scheme 3 and/or are commercially available.Examples of such compounds which are commercially available, for examplefrom Apollo and/or Aldrich and/or Chemical Blocks and/or TCI Europe,include 1-[(2-chloroethyl)sulfonyl]pentane, 2-chloroethyl phenylsulfone, p-toluenesulfonylmethyl chloride,1-[(2-chloroethyl)sulfonyl]-4-methylbenzene, 2-chloroethyl3-[(trifluoromethyl)phenyl]sulfone, 2-chloroethyl 4-fluorophenylsulfone, 2-chloroethyl 4-chlorophenyl sulfone and1-{[(2-chloroethyl)sulfonyl]methyl}benzene, bromomethylphenyl sulfoneand 3,5-bis(trifluoromethyl)phenyl chloromethyl sulfone.

Compounds of formula (III) in which X represents tosylate or mesylatemay be prepared according to Scheme 4.

wherein R¹ and a are as defined hereinabove, and Boc representstert-butoxycarbonyl.

Reagents and Conditions: i) suitable acid e.g. concentrated sulphuricacid, appropriate solvent such as water, sodium 3-nitrobenzenesulfonate(commercially available, for example, from Aldrich), appropriateelevated temperature such as from about 110 to 140° C.; ii) Suzukireaction using a suitable solvent such as DMF and/or tetrahydrofuran(THF), suitable base e.g. potassium carbonate, appropriate catalyst forexample [1,1′-bis(diphenylphosphino) ferrocene palladium (II)] chloride,at an elevated temperature such as from about 70 to 80° C. (for exampleusing microwave radiation); iii) suitable solvent such asN-methylpyrrolidinone (NMP), appropriate base e.g. sodium tert-butoxide,at an elevated temperature for example from about 130 to 150° C.; iv)deprotection using a suitable acid e.g. trifluoracetic acid (TFA) orhydrogen chloride in a suitable solvent such as dichloromethane (DCM),dioxane, iso-propylalcohol or toluene at room termperature.

Alternatively, step ii) in Scheme 1 may be carried out using9-borabicyclo[3.3.1] nonane and an appropriate olefin to make a boroncompound (equivalent to compound (XV)) in situ. The reaction istypically carried out in a suitable solvent such as THF with anappropriate catalyst e.g. 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II). The reaction is carried out in a manner similarto that described by S. Potuzak and D. S. Tan, Tetrahedron Lett.,45:1797-1801, (2004). Olefins are commercially available, for example,from Aldrich and include ethene, 1-propene, 1-butene, 1-pentene and1-hexene.

The compound of formula (XII), 4-bromo-2-fluoroaniline is commerciallyavailable, for example, from Aldrich.

The compound of formula (XIII), glycerol, is commercially available, forexample, from Fluka and/or Aldrich.

The compounds of formula (XV) are commercially available, for examplefrom Aldrich, and include trimethylboron, triethylborane andtributylborane.

Compounds of formula (XVII) are commercially available, for example fromAldrich and include N-tert-butoxycarbonyl-(R)-(−)-3-pyrrolidinol,N-tert-butoxycarbonyl-(S)-(+)-3-pyrrolidinol and tert-butyl4-hydroxy-1-piperidinecarboxylate.

Compounds of formula (XVIII) may also be prepared according to Scheme 2below.

wherein R¹ and a are as defined hereinabove and Boc representstert-butoxycarbonyl.

Reagents and Conditions: i) suitable acid e.g. concentrated sulphuricacid, appropriate solvent such as water, sodium 3-nitrobenzenesulfonate(commercially available, for example, from Aldrich), appropriateelevated temperature such as from about 110 to 140° C.; ii) suitablesolvent such as NMP, appropriate base e.g. sodium tert-butoxide, at anappropriate elevated temperature for example from about 130 to 150° C.;iii) suitable solvent such as THF:NMP (10:1) at an appropriate loweredtemperature e.g. from about 0 to 5° C., using a suitable catalyst forexample iron(III) acetylacetonate, preferably in an inert, water-freeatmosphere.

Alternatively, step (iii) of Scheme 2 may be performed before step (ii)of Scheme 2, thereby first forming a compound of formula (XVI), andsubsequently a compound of formula (XVIII).

The compound of formula (XIX), 4-chloro-2-fluoroaniline, is commerciallyavailable, for example, from Aldrich.

Compounds of formula (XVII) and (XIII) are commercially available, seeabove (after Scheme 1).

Compounds of formula (XXII) are commercially available, for example,from Aldrich and/or TCI-Europe and include methylmagnesium bromide,ethylmagnesium bromide, n-propylmagnesium bromide, n-butylmagnesiumbromide, n-pentylmagnesium bromide and n-hexylmagnesium bromide.

wherein R⁴ is as defined hereinabove, n represents 1 to 6 and (CH₂)_(n)may be optionally substituted by one C₁₋₃alkyl group.

Reagents and Conditions: i) suitable solvent such as DMF, at an elevatedtemperature such as from about 60 to 90° C.; ii) appropriate base e.g.triethylamine, in a suitable solvent for example DCM,methanesulfonylchloride (commercially available, for example, fromAldrich) and optionally in the presence of additional chloride ions e.g.lithium chloride or n-butylammonium chloride; iii) suitable solvent suchas DCM, appropriate oxidising agent e.g. m-chloroperbenzoic acid(commercially available, for example, from Aldrich); iv) appropriatesolvent such as ethanol or DMF, optionally at an appropriate elevatedtemperature e.g. from about 60 to 80° C., followed by treatment with anappropriate oxidising agent e.g. m-chloroperbenzoic acid in a suitablesolvent e.g. DCM; v) suitable solvent such as DMF at an appropriateelevated temperature e.g. from about 60 to 80° C.

Compounds of formula (XXIII) are commercially available, for example,from Aldrich and/or Apollo and/or TCI-Europe, and include2-bromoethanol, 3-bromopropanol, 4-bromobutanol, 5-bromopentanol,6-bromohexanol, 1-bromo-2-propanol, (R)-(−)-3-bromo-2-methyl-1-propanol,(S)-(−)-3-bromo-2-methyl-1-propanol and 1-bromo-2-butanol.

Compounds of formula (XXIV) are commercially available, for example,from Aldrich, and include sodium ethanethiolate, sodium1-propanethiolate, sodium 2-propanethiolate, sodium 1-butanethiolate,sodium 2-methyl-2-propanethiolate, sodium thiophenoxide and sodium4-methylbenzenethiolate.

Compounds of formula (XXIV) may also be prepared in situ, by theaddition of a suitable base, such as sodium hydride to a solution of thecorresponding thiol in a suitable solvent, such as DMF. The suspensionmay be left for an appropriate amount of time, e.g. about 15 min, beforecontinuing with the reactions described in Scheme 3.

Thiol compounds corresponding to compounds of formula (XXIV) arecommercially available, for example, from Aldrich and/or TCI-Europeand/or Apollo, and include methanemercaptan, 2-methyl-2-butanethiol,3-methyl-1-butanethiol, 1-pentanethiol, hexylmercaptan,cyclopentanethiol, cyclohexanethiol, 2-naphthalenethiol, thiophenol,2-bromothiophenol, 4-fluorothiophenol, 2,5-dichlorothiophenol,3-methylbenzenethiol, 2-ethylthiophenol, 2-iso-propylthiophenol,2,4-dimethylthiophenol, benzyl mercaptan, phenylethylmercaptan,2-chlorobenzyl mercaptan, 3-methylbenzyl mercaptan and3,5-bis(trifluoromethyl)thiophenol.

Compounds of formula (XXV) may be prepared as described in Scheme 3, ormay also be commercially available, for example, from TCI-Europe and/orAlfa Aesar and/or Aldrich, and include 2-(ethylthio)ethanol,2-(iso-butylthio)ethanol, 4-(methylthio)-1-butanol,3-(methylthio)-1-hexanol, 2-hydroxyethyl benzyl sulphide, 2-hydroxyethyln-pentyl sulphide, 4-chlorobenzyl 2-hydroxyethyl sulphide and3-(methylthio)-1-propanol.

Compounds of formula (XXVI) are also commercially available, forexample, from Acros and/or Aldrich, and include 2-chloroethyl ethylsulphide and 1-{[(2-chloroethyl)sulfonyl]methyl}benzene

Compounds of formula (XXVII) are commercially available, for example,from TCI-Europe and/or Aldrich and/or Alfa Aesar, and include1-bromo-2-chloroethane, 2-bromo-1-chloropropane,1-bromo-3-chloropropane, 1-bromo-4-chlorobutane,1-bromo-3-chloro-2-methylpropane, 1-bromo-5-chloropentane and1-bromo-6-chlorohexane.

Compounds of formula (XXVIII) are commercially available, for example,from Aldrich, and/or Alfa Aesar and include dibromomethane,1,2-dibromoethane, 1,2-dibromopropane, 1,2-dibromobutane,1,3-dibromopropane, 1,3-dibromobutane, 1,4-dibromobutane,1,4-dibromopentane, 1,5-dibromopentane, 1,5-dibromo-3-methylpentane and1,6-dibromohexane.

wherein R⁴ is as defined hereinabove, n represents 1 to 6, (CH₂)_(n) maybe optionally substituted by one C₁₋₃alkyl group, and X representsmesylate or tosylate.

Reagents and Conditions: i) suitable activating agent for examplemethylsulfonyl chloride or p-toluenesulfonyl chloride (both commerciallyavailable, for example, from Aldrich), suitable solvent such as pyridineor DCM, optionally at a suitable lowered temperature e.g. from about 0to 5° C.; ii) suitable solvent such as DCM, appropriate oxidising agente.g. m-chloroperbenzoic acid; iii) suitable solvent such as DMF,optionally at an appropriate elevated temperature for example from about70 to 80° C.

Compounds of formula (XXIV) and (XXV) are commercially available, seeabove (after Scheme 3).

Compounds of formula (XXIV) may also be prepared in situ, by theaddition of a suitable base, such as sodium hydride to a solution of thecorresponding thiol in a suitable solvent, such as DMF. The suspensionmay be left for an appropriate amount of time, e.g. about 15 min, beforecontinuing with the reactions described in Scheme 4.

Compounds of formula (XXXI) are commercially available, for example,from Aldrich, and include ethylene di(p-toluenesulfonate),(S)-(−)-1,2-propanediol di-p-tosylate, 1,3-propanediol di-p-tosylate and1,4-butanediol dimethanesulfonate. Alternatively, compounds of formula(XXXI) may be prepared by methods well known to those skilled in theart, by activation of the corresponding diol. The reaction may typicallybe carried out using a suitable activating agent such as methanesulfonylchloride, or p-toluenesulfonyl chloride in a suitable solvent such asDCM or pyridine. Diols corresponding to compounds of formula (XXXI) arecommercially available, for example, from Aldrich, and include ethyleneglycol, 1,2-butanediol, 1,3-propanediol, 1,3-butanediol, 1,4-butanediol,1,4-pentanediol, 1,5-pentanediol, 1,5-hexanediol,3-methyl-1,5-pentanediol and 1,6-hexanediol.

Compounds of formula (XXXII) are commercially available, for example,from Aldrich and/or Alfa Aesar, and include 2-(methylsulfonyl)ethanoland 2-(ethanesulfonyl)ethanol.

In an alternative preparation, the compounds of formula (XXV) which areHO—(CH₂)₂CH(Y)SR⁴ may be prepared according to Scheme 5 below:

wherein R⁴ is as defined hereinabove and Y represents hydrogen orC₁₋₃alkyl.

Reagents and Conditions: i) suitable solvent such as DMF; ii) suitablesolvent such as THF, appropriate reducing agent e.g. lithium aluminiumhydride solution in ether, suitable lowered temperature such as fromabout 0 to 5° C.

The compounds of formula (XXXIII) are commercially available, forexample from Aldrich and/or Alfa Aesar and/or Rarechem, and includeethyl acrylate, ethyl crotonate, ethyl trans-2-pentenoate, ethyl4-methyl-trans-2-pentenoate and ethyl trans-2-hexenoate.

Compounds of formula (XXIV) are commercially available, see above (afterScheme 3).

According to a second process, B, a compound of formula (I) in which R²represents a saturated 5 to 7 membered ring containing one SO₂ group orR² represents ethylene-SO₂—R⁴ may be prepared by reacting a compound offormula (II)

with a compound of formula (IV) or (IVa)

wherein R¹, a and R⁴ are as defined hereinabove and m represents 1 to 3.

The reaction may typically be carried out in a suitable solvent, such asTHF or DMF. Optionally, an appropriate base may be added, for examplesodium bicarbonate. The reaction is typically heated for example using amicrowave oven at a suitable temperature from about 100 to 150° C. foran appropriate time, such as about 15 to 30 min. Alternatively, theheating may be conducted using conventional methods at a suitableelevated temperature, such as from about 70 to 90° C. for longer periodsof time, e.g. about 2 to 3 hours or overnight.

Compounds of formula (II) may be prepared according to Scheme 1 above.

Compounds of formula (IV) may be commercially available or may beprepared according to methods disclosed herein. 2,3-dihydrothiophene1,1-dioxide is commercially available, for example, from AKOS.3,4-dihydro-2H-thiopyran 1,1-dioxide may be prepared according to themethods disclosed by X-F. Ren, E. Turos, C. H. Lake and M. R. Churchill,J. Org. Chem., 60:6468-6483, (1995), see page 6483.2,3,4,5-tetrahydrothiepin 1,1-dioxide may be prepared according to themethods disclosed by B. F. Bonini, M. Comes-Franchini, M. Fochi, G.Mazzanti, A. Ricci, Tetrahedron, 52:4803-4816, (1996), see compound 12.

Compounds of formula (IVa) are commercially available, for example, fromAldrich, and include methyl vinyl sulfone, ethyl vinyl sulfone andphenyl vinyl sulfone.

According to a third process, C, a compound of formula (I) in which R³represents —N(R⁵)SO₂— may be prepared by reacting a compound of formula(V)

with a compound of formula (VI)

wherein R¹, a, R⁴ and R⁵ are as defined hereinabove, n represents 1 to 6and (CH₂)_(n) may be optionally substituted by one C₁₋₃alkyl group.

The reaction may typically be carried out using a suitable solvent suchas DCM with a suitable base e.g. triethylamine.

Compounds of formula (V) may be prepared according to the followingreaction schemes (Schemes 6, 6a and 7).

Compounds of formula (VI) are commercially available, for example, fromAldrich and/or TCI Europe and/or Apollo International and/or Fluorochem,and include methanesulfonyl chloride, ethanesulfonylchloride,1-propanesulfonyl chloride, iso-propylsulfonyl chloride,2-methyl-1-propylsulfonyl chloride, 1-butanesulfonyl chloride,sec-butylsulfonyl chloride, n-pentylsulfonyl chloride, 2-pentylsulfonylchloride, 1-hexanesulfonyl chloride, cyclopentanesulfonyl chloride,cyclohexanesulfonyl chloride, cyclopentylmethanesulfonyl chloridecyclohexylmethanesulfonyl chloride, benzenesulfonyl chloride,1-naphthalenesulfonyl chloride, 2-naphthalenesulfonyl chloride,2-anthracenesulfonyl chloride, 4-ethylbenzenesulfonyl chloride,4-n-propylbenzenesulfonyl chloride, 4-iso-propylbenzenesulfonylchloride, 4-bromobenzenesulfonyl chloride, 4-iodobenzenesulfonylchloride, 3-(trifluoromethyl)benzenesulfonyl chloride,4-cyanobenzenesulfonylchloride, 2,5-dichlorobenzenesulfonyl chloride,2-chloro-4-cyanobenzenesulfonyl chloride, benzylsulfonyl chloride,2-(1-naphthyl)ethanesulfonyl chloride, 2-phenyl-ethanesulfonyl chloride,4-chlorobenzylsulfonyl chloride, 4-methylbenzylsulfonyl chloride,2-trifluoromethylbenzylsulfonyl chloride and2-(4-chlorophenyl)-ethanesulfonyl chloride.

wherein R¹, a and R⁵ are as defined hereinabove, and X represents asuitable leaving group such as chlorine, broming or iodine.

Reagents and Conditions: i) suitable solvent such as 2-butanone,appropriate base e.g. potassium carbonate, at an elevated temperaturesuch as from about 70 to 90° C.; ii) suitable, solvent such as ethanol,hydrazine or hydrazine monohydrate, at an elevated temperature such asfrom about 70 to 90° C.; iii) 1 equivalent of R⁵—X (XXXVIIa), in anappropriate solvent such as DMF, suitable base such as triethylamine orsodium hydride, optionally with an activating agent such as sodiumiodide; or reductive amination using R⁵═O (XXXVIIb), in a suitablesolvent e.g. DMF, suitable reducing agent such as sodiumtriacetoxyborohydride.

The compound of formula (XXXV),2-(2-bromoethyl)-1H-isoindole-1,3(2H)-dione is commercially available,for example from Acros and/or Aldrich.

Compounds of formula (XXXVIIa) are commercially available, for examplefrom Aldrich, and include methyl iodide, iodoethane, 1-iodopropane,1-iodobutane, 1-iodopentane and 1-iodohexane.

Compounds of formula (XXXVIIb) are commercially available, for example,from Aldrich, and include formaldehyde, acetaldehyde, propionaldehyde,methyl ethyl ketone, butyraldehyde, valeraldehyde, 3-pentanone, hexanal,3-hexanone and 3-methyl-3-pentanone.

wherein R¹ and a are as defined hereinabove, n represents 2 to 6 andR^(a) represents C₁₋₆alkyl.

Reagents and Conditions: i) 2-benzofuran-1,3-dione (commerciallyavailable, for example, from Aldrich) in a suitable solvent such astoluene; ii) suitable solvent such as toluene, appropriate base e.g.triethylamine; iii) suitable solvent such as DMF, appropriate base e.g.DIPEA and/or tributylammonium iodide, optionally with an appropriateactivating agent e.g. sodium iodide, optionally at an elevatedtemperature such as from about 70 to 90° C.; iv) suitable solvent suchas ethanol, hydrazine or hydrazine monohydrate, at an elevatedtemperature such as from about 70 to 90° C.

The compounds of formula (XXXVa), are commercially available, forexample from Aldrich.

The compounds of formula (XXXVd) are commercially available, for examplefrom Aldrich and/or Fluka.

wherein R¹, a and R⁵ are as defined hereinabove, X represents a suitableleaving group such as chlorine, bromine or iodine, n represents 1 to 6and (CH₂)_(n) may be optionally substituted by one C₁₋₃alkyl group.

Reagents and Conditions: i) suitable solvent such as 2-butanone,appropriate base e.g. potassium carbonate, at an elevated temperaturesuch as from about 70 to 90° C.; ii) deprotection using a suitable acidsuch as hydrogen chloride or TFA in a suitable solvent e.g. dioxane orDCM; iii) 1 equivalent of R⁵—X (XXXVIIa), in an appropriate solvent suchas DMF, suitable base such as triethylamine or sodium hydride,optionally with an activating agent such as sodium iodide; or reductiveamination using R⁵═O (XXXVIIb), in a suitable solvent e.g. DMF, suitablereducing agent such as sodium triacetoxyborohydride.

Compounds of formula (XXXVIII) are commercially available, for example,from Aldrich and/or Toronto Chemicals, and include 2-(Boc-amino)ethylbromide, 3-(Boc-amino)propyl bromide, 4-(Boc-amino)butyl bromide,5-(Boc-amino)pentyl bromide and 6-(Boc-amino)hexyl bromide.

Compounds of formula (XXXVIIa) and (XXXVIIb) are commercially available,see above (after Scheme 6).

According to a fourth process, D, a compound of formula (I) in which R³represents —N(R⁵)SO₂— may be prepared by reacting a compound of formula(II)

with a compound of formula (VII)

wherein R¹, a, R⁴ and R⁵ are as defined hereinabove, n represents 1 to6, (CH₂), may be optionally substituted by one C₁₋₃alkyl group, and Xrepresents a suitable leaving group such as chlorine, bromine, tosylateor mesylate.

The reaction may typically be carried out using a suitable base such assodium hydrogen carbonate, with an appropriate activating agent e.g.sodium iodide, in a suitable solvent such as DMF. The reaction istypically heated for example, using a microwave oven at an appropriateelevated temperature for example from about 140 to 160° C., for about 10to 30 minutes, as appropriate. Alternatively, heating may be withconventional apparatus, at elevated temperatures for example from about50 to 70° C., for about 3 hours to overnight, as appropriate.

Compounds of formula (II) may be prepared according to Scheme 1 above.

Compounds of formula (VII) in which X represents chlorine or bromine arecommercially available, for example, from Apollo, and includeN-(2-bromoethyl)-4-chlorobenzene-1-sulfonamide,N-(2-bromoethyl)-4-fluorobenzene-1-sulphonamide,N-(2-bromoethyl)-3-(trifluoromethyl)benzene-1-sulphonamide,N-(2-bromoethyl)-2,4-dichlorobenzene sulfonamide and4-Bromo-N-(3-chloropropyl)benzene sulphonamide.

Compounds of formula (VII) in which X represents mesylate or tosylatemay be prepared according to Scheme 8 below.

wherein R⁴ and R⁵ are as defined hereinabove, n represents 1 to 6 and(CH₂)_(n) may be optionally substituted by one C₁₋₃alkyl group.

Reagents and Conditions: i) suitable solvent such as DCM, appropriatebase e.g. triethylamine, at a lowered temperature such as from about 0°C. to room temperature.

Compounds of formula (VI) are commercially available, see above(described after process C).

Compounds of formula (XL) are commercially available, for example, fromAldrich and/or TCI Europe, and include 2-aminoethanol,2-(methylamino)ethanol, 2-(ethylamino)ethanol, 2-(propylamino)ethanol,2-(butylamino)ethanol, 2-(n-pentylamino)ethanol, 3-amino-1-propanol,3-(methylamino)-1-propanol, 4-amino-1-butanol,(R)-4-amino-2-methyl-1-butanol, 4-ethylamino-1-butanol,4-(n-butylamino)-1-butanol, 5-amino-1-pentanol and 6-amino-1-hexanol.

According to a fifth process, E, a compound of formula (I) in which R³represents —SO₂N(R⁶)— may be prepared by reacting a compound of formula(II)

with a compound of formula (VIII)

wherein R¹, a, R⁴ and R⁶ are as defined hereinabove, n represents 1 to6, (CH₂)_(n) may be optionally substituted by one C₁₋₃alkyl group, and Xrepresents a suitable leaving group such as chlorine or bromine.

The reaction may typically be carried out using a suitable solvent suchas DMF with an appropriate activating agent for example, sodium iodide,with a suitable base, e.g. potassium carbonate. The reaction is usuallyheated using conventional apparatus, at an appropriate elevatedtemperature for example from about 50 to 70° C., for about 3 hours toovernight, as appropriate.

Compounds of formula (II) may be prepared according to Scheme 1 above.

Compounds of formula (VIII) may be prepared according to Scheme 9 below.

wherein R⁴ and R⁶ are as defined hereinabove, n represents 1 to 6 and(CH₂), may be optionally substituted by one C₁₋₃alkyl group.

Reagents and Conditions: i) suitable solvent such as DCM, at a loweredtemperature e.g. from about 0° C. to room temperature.

Compounds of formula (XLI) are commercially available, for example, fromAldrich and/or TCI Europe, and include 2-chloroethanesulfonyl chlorideand 3-chloropropanesulfonyl chloride.

Compounds of formula (XI) are commercially available, for example, fromAldrich and/or ABCR and/or Enamine and/or Chembridge, and includemethylamine, ethylamine, propylamine, butylamine, (R)-(−)-2-aminobutane,(S)-(+)-2-aminobutanepentylamine, tert-butylamine,1,1-dimethylpropylamine, hexylamine, dimethylamine, N-ethylmethylamine,N-methylpropylamine, diethylamine, dipropylamine, N-ethylbutylamine,dibutylamine, dipentylamine, dihexylamine, cyclopentylamine,cyclohexylamine, 2-methylcyclohexylamine, cycloheptylamine,N-methylcyclohexylamine, N-isopropylcyclohexyamine,N-cycloheptyl-N-methylamine, N-(sec-butyl)cycloheptanamine,N-(1-ethylpropyl)cycloheptanamine, N-isopropylcycloheptanamine,cyclohexanemethylamine, cycloheptanemethylamine, 2-cyclohexylethylamine,aniline, 9-aminophenanthrene, 1-aminoanthracene, 2-aminobenzonitrile,2-fluoroaniline, 4-chloroaniline, 3-bromoaniline, 3-iodoaniline,1-amino-2-methylnaphthalene, 2-methylaniline, 3-ethylaniline,4-propylaniline, 2-isopropylaniline, 2-aminobenzotrifluoride,3,5-bis(trifluoromethyl)aniline, 3-amino-4-fluorobenzotrifluoride,5-fluoro-2-methylaniline, N-ethyl-1-naphthalene, N-methylaniline,N-ethylaniline, N-butylaniline, N-hexylaniline, N-ethyl-3-methylaniline,benzylamine, 2-phenylethylamine, 2-(3-chlorophenyl)ethylamine,3-phenylpropylamine, (3-phenylpropyl)methylamine,N-methylphenethylamine, (2-phenylethyl)propylamine, cyclopentylamine,cyclohexylamine, cycloheptylamine, morpholine, thiomorphline, piperazineand N-methylpiperazine.

According to a sixth process, F, a compound of formula (I) in which R³represents —N(R⁷)C(O)N(R⁸)—, and R⁸ represents hydrogen, may be preparedby reacting a compound of formula (Va)

with a compound of formula (IX)

R⁴—N═C═O  (IX)

wherein R¹, a, R⁴ and R⁷ are as defined hereinabove, n represents 1 to 6and (CH₂)_(n) may be optionally substituted by one C₁ alkyl group.

The reaction may typically be carried out using a suitable solvent, suchas DCM. The reaction is usually carried out at ambient temperature foran appropriate length of time such as overnight, for example.

Compounds of formula (Va) may be prepared according to Schemes 6 and 7above, in which R⁵ is R⁷.

Compounds of formula (IX) are commercially available, for example, fromAldrich, and include ethyl isocyanate, isopropyl isocyanate, propylisocyanate, butyl isocyanate, sec-butyl isocyanate, tert-butylisocyanate, pentyl isocyanate, hexyl isocyanate, cyclopentyl isocyanate, cyclohexyl isocyanate, cycloheptyl isocyanate, cyclohexanemethylisocyanate, (R)-(−)-1-cyclohexylethyl isocyanate, phenyl isocyanate,3-chlorophenyl isocyanate, 2-fluoro-phenyl isocyanate, 2-bromophenylisocyanate, 4-iodophenyl isocyanate, 4-methylphenyl isocyanate,2-ethylphenyl isocyanate, 2-isopropylphenyl isocyanate,2-(trifluoromethyl)phenyl isocyanate, 3-cyanophenyl isocyanate,2,3-dimethylphenyl isocyanate, 3-chloro-4-methylphenyl isocyanate,4-bromo-2-(trifluoromethyl)phenyl isocyanate, 2-isopropyl-6-methylphenylisocyanate, benzyl isocyanate, phenethyl isocyanate, 3-phenylpropylisocyanate, (S)-(−)-1-phenylpropyl isocyanate, 3-methylbenzylisocyanate, 4-fluorobenzyl isocyanate, 2,4-dichlorobenzyl isocyanate and4-ethylphenethyl isocyanate.

According to a seventh process, G, a compound of formula (I) in which R³represents —N(R⁷)C(O)N(R⁸)— may be prepared by reacting a compound offormula (X)

with a compound of formula (Xla)

wherein R¹, a, R⁴, R⁷ and R⁸ are as defined hereinabove, n represents 1to 6 and (CH₂)_(n) may be optionally substituted by one C₁₋₃alkyl group.

The reaction may typically be carried out in a suitable solvent such asTHF or DCM, usually at an elevated temperature for example at reflux.

Compounds of formula (X) may be prepared according to Scheme 10 below.

Compounds of formula (XIa) are commercially available, for which seecompounds of formula (XI) in which R⁶ is R⁸ (see after Scheme 9, above).

wherein R¹, a and R⁷ are as defined hereinabove, n represents 1 to 6 and(CH₂)_(n) may be optionally substituted by one C₁₋₃alkyl group.

Reagents and Conditions: i) 1 equivalent 1,1′-carbonyldiimidazole, in anappropriate solvent such as THF or DCM.

Compounds of formula (Va) may be prepared according to Schemes 6 and 7above, in which R⁵ is R⁷.

The compound of formula (XLII), 1,1′-carbonyldiimidazole, iscommercially available, for example, from Aldrich.

According to an eighth process, H, a compound of formula (I), may beprepared by interconversion from other compounds of formula (I).

Interconversions include, but are not limited to alkylation anddeprotection, under standard conditions well known to those skilled inthe art.

Thus, typically, an alkylation reaction may be carried out between acompound of formula (I) and a C₁₋₆alkyl, activated to substitution bymeans of a leaving group such as halogen, such as chlorine or bromine,or an activated hydroxyl group, such as mesylate or tosylate. Thereaction usually takes place in the presence of a suitable base such astriethylamine, N,N′ diisopropylethylamine or sodium hydride, in anappropriate solvent such as 2-butanone or DMF, optionally at anappropriate elevated temperature such as at about 80° C.

According to a ninth process, I, a salt of a compound of formula (I) maybe prepared by exchange of counterions, or precipitation of said saltfrom the free base.

Compounds of formula (I) may be further purified by methods well-knownto those skilled in the art, for example by recrystallisation, columnchromatography (which may be manual or automated, for examplemass-directed), preparative TLC and the like. A suitable solvent systemfor recrystallisation of compounds of formula (I) in which R³ represents—N(R⁵)SO₂— and R⁴ represents C₁₋₆alkyl is methanol/ethyl acetate.

Examples of protecting groups that may be employed in the syntheticroutes described and the means for their removal can be found in T. W.Greene et al. ‘Protective Groups in Organic Synthesis’ (3rd edition, J.Wiley and Sons, 1999). Suitable amine protecting groups include sulfonyl(e.g. tosyl), acyl (e.g. acetyl, 2′,2′,2′-trichloroethoxycarbonyl,benzyloxycarbonyl or t-butoxycarbonyl) and arylalkyl (e.g. benzyl),which may be removed by hydrolysis (e.g. using an acid such as hydrogenchloride in dioxane or trifluoroacetic acid in dichloromethane) orreductively (e.g. hydrogenolysis of a benzyl group or reductive removalof a 2′,2′,2′-trichloroethoxycarbonyl group using zinc in acetic acid)as appropriate. Other suitable amine protecting groups includetrifluoroacetyl (—COCF₃), which may be removed by base catalysedhydrolysis or a solid phase resin bound benzyl group, such as aMerrifield resin bound 2,6-dimethoxybenzyl group (Ellman linker), whichmay be removed by acid cleavage, for example with trifluoroacetic acid.

It will be appreciated that novel intermediates described herein formanother embodiment of the present invention.

Examples of disease states in which a compound of formula (I), or apharmaceutically acceptable salt thereof potentially may have beneficialanti-inflammatory and/or anti-allergic effects include inflammatoryand/or allergic diseases of the respiratory tract, such as allergicrhinitis (seasonal and perennial) or other diseases such as bronchitis(including chronic bronchitis), asthma (including allergen-inducedasthmatic reactions), chronic obstructive pulmonary disease (COPD) andsinusitis.

Furthermore, the compounds of formula (I) may be of use in the treatmentof nephritis, skin diseases such as psoriasis, eczema, allergicdermatitis and hypersensitivity reactions. Also, the compounds offormula (I) may be useful in the treatment of insect bites and stings.

The compounds of formula (I) may also be of use in the treatment ofnasal polyposis, conjunctivitis (e.g allergic conjunctivitis) orpruritis.

A disease of particular interest is allergic rhinitis.

Other diseases in which histamine may have a pathophysiological roleinclude non-allegic rhinitis, and also diseases of the gastrointestinaltract such as intestinal inflammatory diseases including inflammatorybowel disease (e.g. Crohn's disease or ulcerative colitis) andintestinal inflammatory diseases secondary to radiation exposure orallergen exposure.

It will be appreciated by those skilled in the art that referencesherein to treatment or therapy may extend to prophylaxis as well as thetreatment of established conditions.

As mentioned above, compounds of formula (I) may be useful astherapeutic agents. There is thus provided a compound of formula (I) ora pharmaceutically acceptable salt thereof for use in therapy.

In another embodiment, there is provided a compound which is6-butyl-8-({1-[3-(ethylsulfonyl)propyl]-4-piperidinyl}oxy)quinoline, ora pharmaceutically acceptable salt thereof for use in therapy.

In another embodiment, there is provided a compound which isN-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide,or a pharmaceutically acceptable salt (such as the dihydrochloride salt)thereof for use in therapy.

In another embodiment, there is provided a compound of formula (I) or apharmaceutically acceptable salt thereof for use in the treatment of anyof the above diseases (e.g. allergic rhinitis).

In another embodiment, there is provided a compound which is6-butyl-8-({1-[3-(ethylsulfonyl)propyl]-4-piperidinyl}oxy)quinoline, ora pharmaceutically acceptable salt thereof for use in the treatment ofany of the above diseases (e.g. allergic rhinitis).

In another embodiment, there is provided a compound which isN-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide,or a pharmaceutically acceptable salt (such as the dihydrochloride salt)thereof for use in the treatment of any of the above diseases (e.g.allergic rhinitis).

In another embodiment, there is provided the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof for themanufacture of a medicament for the treatment of any of the abovediseases (e.g. allergic rhinitis).

In another embodiment, there is provided the use of a compound which is6-butyl-8-({1-[3-(ethylsulfonyl)propyl]-4-piperidinyl}oxy)quinoline, ora pharmaceutically acceptable salt thereof for the manufacture of amedicament for the treatment of any of the above diseases (e.g. allergicrhinitis).

In another embodiment, there is provided the use of a compound which isN-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide,or a pharmaceutically acceptable salt (such as the dihydrochloride salt)thereof for the manufacture of a medicament for the treatment of any ofthe above diseases (e.g. allergic rhinitis).

In another embodiment, there is provided a method for the treatment (orprophylaxis) of any of the above diseases (for example inflammatoryand/or allergic diseases of the respiratory tract, e.g. allergicrhinitis), in a patient in need thereof, which method comprisesadministering an effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof.

In another embodiment, there is provided a method for the treatment (orprophylaxis) of any of the above diseases (for example inflammatoryand/or allergic diseases of the respiratory tract, e.g. allergicrhinitis), in a patient in need thereof, which method comprisesadministering an effective amount of a compound which is6-butyl-8-({1-[3-(ethylsulfonyl)propyl]-4-piperidinyl}oxy)quinoline, ora pharmaceutically acceptable salt thereof.

In another embodiment, there is provided a method for the treatment (orprophylaxis) of any of the above diseases (for example inflammatoryand/or allergic diseases of the respiratory tract, e.g. allergicrhinitis), in a patient in need thereof, which method comprisesadministering an effective amount of a compound which isN-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide,or a pharmaceutically acceptable salt (such as the dihydrochloride salt)thereof.

When used in therapy, the compounds of formula (I) or pharmaceuticallyacceptable salts thereof may typically be formulated in a suitablepharmaceutical composition. Such pharmaceutical compositions may beprepared using standard procedures.

Thus, there is provided a composition which comprises a compound offormula (I) or a pharmaceutically acceptable salt thereof and one ormore (e.g. 10 or fewer) pharmaceutically acceptable carriers and/orexcipients.

In another embodiment, there is provided a composition which comprises acompound which is6-butyl-8-({1-[3-(ethylsulfonyl)propyl]-4-piperidinyl}oxy)quinoline, ora pharmaceutically acceptable salt thereof and one or morepharmaceutically acceptable carriers and/or excipients.

In another embodiment, there is provided a composition which comprises acompound which isN-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide,or a pharmaceutically acceptable salt (such as the dihydrochloride salt)thereof and one or more pharmaceutically acceptable carriers and/orexcipients.

A composition comprising a compound of formula (I) or a pharmaceuticallyacceptable salt thereof, which may be prepared by admixture, suitably atambient temperature and atmospheric pressure, may be suitable fortopical administration (which includes epicutaneous, inhaled, intranasalor ocular administration), enteral administration (which includes oralor rectal administration) or parenteral administration (such as byinjection or infusion). Of interest are compositions comprising acompound of formula (I) or a pharmaceutically acceptable salt thereof,suitable for topical administration, particularly suitable forintranasal administration.

Generally, compositions may be in the form of solutions or suspensions(aqueous or non-aqueous), tablets, capsules, oral liquid preparations,powders, granules, lozenges, lotions, creams, ointments, gels, foams,reconstitutable powders or suppositories as required by the route ofadministration.

Generally, the compositions comprising a compound of formula (I) or apharmaceutically acceptable salt thereof may contain from about 0.001 to99% (w/w), or about 0.1 to 99% (w/w), such as from about 0.1 to 60%(w/w), or about 10 to 60% (w/w), or about 0.01% to 2% (w/w) (based onthe total weight of the composition), of the compound of formula (I) orthe pharmaceutically acceptable salt thereof, depending on the route ofadministration. The dose of the compound used in the treatment of theaforementioned diseases will vary in the usual way with the seriousnessof the diseases, the weight of the sufferer, and other similar factors.However, as a general guide, suitable unit doses may be about 0.05 to1000 mg, for example about 0.05 to 200 mg, for example about 0.05 to 2mg, or about 0.05 to 1 mg and such unit doses may be administered morethan once a day, for example two or three times a day or as desired.Such therapy may extend for a number of weeks or months.

The proportion of the compound of formula (I) or a pharmaceuticallyacceptable salt thereof in a topical composition will depend on theprecise type of composition to be prepared and the particular route ofadministration, but will generally be within the range of from about0.001 to 10% (w/w), based on the total weight of the composition.Generally, however for most types of preparations the proportion usedwill be within the range of from about 0.005 to 1% (w/w), such as about0.01 to 1% (w/w), or about 0.025 to 0.9% (w/w) (based on the totalweight of the composition). However, in powders for inhalation theproportion used will generally be within the range of from about 0.1 to5% (w/w), based on the total weight of the composition.

Generally, compositions suitable for intranasal or inhaledadministration may conveniently be formulated as aerosols, solutions,suspensions, drops, gels or dry powders, optionally with one or morepharmaceutically acceptable carriers and/or excipients such as aqueousor non-aqueous vehicles, thickening agents, isotonicity adjustingagents, antioxidants, preservatives and/or co-solvents.

For compositions suitable for intranasal or inhaled administration, thecompound of formula (I) or a pharmaceutically acceptable salt thereofmay typically be in a particle-size-reduced form, which may be preparedby conventional techniques, for example, micronisation, milling and/ormicrofluidisation. Generally, the size-reduced (e.g. micronised)compound of formula (I) or a pharmaceutically acceptable salt thereofcan be defined by a D₅₀ value of about 0.5 to 10 microns, for example ofabout 1 to 10 microns, such as of about 2 to 4 microns (for example asmeasured using laser diffraction).

In one embodiment, compositions comprising a compound of formula (I) ora pharmaceutically acceptable salt thereof are suitable for intranasaladministration. Intranasal compositions comprising a compound of formula(I) or a pharmaceutically acceptable salt thereof may permit thecompound(s) to be delivered to all areas of the nasal cavities (thetarget tissue) and further, may permit the compound(s) to remain incontact with the target tissue for longer periods of time. A suitabledosing regime for intranasal compositions would be for the patient toinhale slowly through the nose subsequent to the nasal cavity beingcleared. During inhalation the composition would be administered to onenostril while the other is manually compressed. This procedure wouldthen be repeated for the other nostril. Typically, one or twoadministrations per nostril would be administered by the above procedureup to two or three times each day, ideally once daily. Of particularinterest are intranasal compositions suitable for once dailyadministration.

The intranasal compositions containing a compound of formula (I) or apharmaceutically acceptable salt thereof may be in the form of anaqueous suspension and/or an aqueous solution. Partial suspensionsand/or partial solutions are encompassed within the scope of the presentinvention. Compositions comprising one compound which is in solution andanother compound which is in suspension are also included within thescope of the present invention.

Intranasal compositions may optionally contain one or moresuspending/thickening agents, one or more preservatives, one or morewetting agents, one or more isotonicity adjusting agents and/or one ormore co-solvents as desired. Compositions suitable for intranasaladministration may optionally further contain other excipients, such asantioxidants (for example sodium metabisulphite), taste-masking agents(such as menthol) and sweetening agents (for example dextrose, glycerol,saccharin and/or sorbitol).

The skilled person would readily appreciate that some excipients mayperform more than one function, depending on the nature and number ofexcipients used in the composition and the particular properties of thetherapeutic compound(s) and other carriers and/or excipients containedtherein.

The suspending/thickening agent(s), if included, will typically bepresent in the intranasal composition in an amount of between about 0.1and 5% (w/w), such as between about 1.5% and 2.4% (w/w), particularlyabout 2.4% (w/w) based on the total weight of the composition. Examplesof suspending agents include, but are not limited to Avicela(microcrystalline cellulose and carboxymethylcellulose sodium),carboxymethylcellulose sodium, veegum, tragacanth, bentonite,methylcellulose, xanthan gum, carbopol and polyethylene glycols. In oneembodiment, an intranasal composition containing a compound of formula(I) or a pharmaceutically acceptable salt thereof comprises asuspending/thickening agent which is microcrystalline cellulose andcarboxymethylcellulose sodium. Suspending agents may also be included incompositions suitable for inhaled, ocular and oral administration asappropriate.

For stability purposes, intranasal compositions comprising a compound offormula (I) or a pharmaceutically acceptable salt thereof may beprotected from microbial or fungal contamination and growth by inclusionof a preservative. Examples of pharmaceutically acceptableanti-microbial agents or preservatives include, but are not limited toquaternary ammonium compounds (e.g. benzethonium chloride, cetrimide,cetylpyridinium chloride, myristal picolinium chloride and lauralkoniumchloride. Another anti-microbial agent is benzalkonium chloride),mercurial agents (e.g. phenylmercuric nitrate, phenylmercuric acetateand thimerosal), alcoholic agents (e.g. chlorobutanol, phenylethylalcohol and benzyl alcohol), antibacterial esters (e.g. esters ofpara-hydroxybenzoic acid), chelating agents such as disodiumethylenediaminetetraacetate (EDTA) and other anti-microbial agents suchas chlorhexidine, chlorocresol, sorbic acid and its salts (such aspotassium sorbate) and polymyxin. Examples of pharmaceuticallyacceptable anti-fungal agents or preservatives may include, but are notlimited to, sodium benzoate, sorbic acid, sodium propionate, methylparaben, ethyl paraben, propyl paraben and butyl paraben. Thepreservative, if included, may be present in an amount of between about0.001 and 1% (w/w), such as about 0.015% (w/w), and for example betweenabout 0.015% to 0.5% (w/w) or between about 0.015 to 0.3% (w/w), basedon the total weight of the composition. In one embodiment, an intranasalcomposition containing a compound of formula (I) or a pharmaceuticallyacceptable salt thereof comprises a preservative which is selected fromEDTA and/or potassium sorbate. Preservatives may be included incompositions suitable for other routes of administration as appropriate.

Compositions which contain a suspended medicament may include apharmaceutically acceptable wetting agent which functions to wet theparticles of medicament to facilitate dispersion thereof in the aqueousphase of the composition. Typically, the amount of wetting agent usedwill not cause foaming of the dispersion during mixing. Examples ofwetting agents include, but are not limited to fatty alcohols, estersand ethers, such as polyoxyethylene (20) sorbitan monooleate(Polysorbate 80), macrogol ethers and poloxamers. The wetting agent maybe present in intranasal compositions in an amount of between about0.005 to 0.05% (w/w), such as between about 0.001 and 0.05% (w/w), forexample about 0.025% (w/w), based on the total weight of thecomposition. In one embodiment, an intranasal composition containing acompound of formula (I) or a pharmaceutically acceptable salt thereofcomprises a wetting agent which is polyoxyethylene (20) sorbitanmonooleate (Polysorbate 80). Wetting agents may be included incompositions suitable for other routes of administration, e.g. forinhaled and/or ocular administration, as appropriate.

An isotonicity adjusting agent may be included to achieve isotonicitywith body fluids e.g. fluids of the nasal cavity, resulting in reducedlevels of irritancy. Examples of isotonicity adjusting agents include,but are not limited to sodium chloride, dextrose, xylitol and calciumchloride. An isotonicity adjusting agent may be included in intranasalcompositions in an amount of between about 0.1 and 10% (w/w), forexample between about 4.5 to 5.5% (w/w), such as about 5.0% (w/w), orbetween about 0.5 to 1% (w/w), or about 0.75% (w/w), based on the totalweight of the composition. In one embodiment, an intranasal compositioncontaining a compound of formula (I) or a pharmaceutically acceptablesalt thereof comprises an isotonicity adjusting agent which is xylitol.In another embodiment, the intranasal composition does not contain anisotonicity adjusting agent. Isotonicity adjusting agents may also beincluded in compositions suitable for other routes of administration,for example in compositions suitable for inhaled, ocular, oral liquidand parenteral administration, as appropriate.

One or more co-solvent(s) may be included to aid solubility of theactive compound(s) and/or other excipients. Examples of pharmaceuticallyacceptable co-solvents include, but are not limited to, propyleneglycol, dipropylene glycol, ethylene glycol, glycerol, ethanol,polyethylene glycols (for example PEG300 or PEG400) and methanol. Theco-solvent(s), if present, may be included in an amount of from about0.05 to 20% (w/w), such as from about 1.5 to 17.5% (w/w), or from about1.5 to 7.5% (w/w), or from about 0.05% to 0.5% (w/w) based on the totalweight of the composition. In one embodiment, an intranasal compositioncontaining a compound of formula (I) or a pharmaceutically acceptablesalt thereof comprises a co-solvent which is propylene glycol.Co-solvents may also be included in compositions suitable for otherroutes of administration, as appropriate.

Further, the intranasal compositions comprising a compound of formula(I) or a pharmaceutically acceptable salt thereof may be buffered by theaddition of suitable buffering agents such as sodium citrate, citricacid, trometarol, phosphates such as disodium phosphate (for example thedodecahydrate, heptahydrate, dihydrate and anhydrous forms) or sodiumphosphate and mixtures thereof. In one embodiment, an intranasalcomposition containing a compound of formula (I) or a pharmaceuticallyacceptable salt thereof comprises buffering agents which are sodiumcitrate and/or citric acid. Buffering agents may also be included incompositions suitable for other routes of administration as appropriate.

In one embodiment, there is provided an intranasal aqueous compositoncontaining a compound of formula (I) or a pharmaceutically acceptablesalt thereof and further comprising

-   -   a) a suspending/thickening agent;    -   b) a preservative;    -   c) a wetting agent;    -   d) a co-solvent; and optionally    -   e) an isotonicity adjusting agent.

Compositions for administration topically to the nose (for example, forthe treatment of rhinitis) or to the lung, include pressurised aerosolcompositions and aqueous compositions delivered to the nasal cavities bypressurised pump. Compositions which are non-pressurised and aresuitable for administration topically to the nasal cavity are ofparticular interest. Suitable compositions contain water as the diluentor carrier for this purpose. Aqueous compositions for administration tothe lung or nose may be provided with conventional excipients such asbuffering agents, tonicity modifying agents and the like. Aqueouscompositions may also be administered to the nose by nebulisation.

A fluid dispenser may typically be used to deliver a fluid compositionto the nasal cavities. The fluid composition may be aqueous ornon-aqueous, but typically aqueous. Such a fluid dispenser may have adispensing nozzle or dispensing orifice through which a metered dose ofthe fluid composition is dispensed upon the application of auser-applied force to a pump mechanism of the fluid dispenser. Suchfluid dispensers are generally provided with a reservoir of multiplemetered doses of the fluid composition, the doses being dispensable uponsequential pump actuations. The dispensing nozzle or orifice may beconfigured for insertion into the nostrils of the user for spraydispensing of the fluid composition into the nasal cavity. A fluiddispenser of the aforementioned type is described and illustrated inWO05/044354 the entire content of which is hereby incorporated herein byreference. The dispenser has a housing which houses a fluid dischargedevice having a compression pump mounted on a container for containing afluid composition. The housing has at least one finger-operable sidelever which is movable inwardly with respect to the housing to cam thecontainer upwardly in the housing to cause the pump to compress and pumpa metered dose of the composition out of a pump stem through a nasalnozzle of the housing. In one embodiment, the fluid dispenser is of thegeneral type illustrated in FIGS. 30-40 of W005/044354.

Aqueous compositions containing a compound of formula (I) or apharmaceutically acceptable salt thereof may also be delivered by a pumpas disclosed in WO2007/138084, for example as disclosed with referenceto FIGS. 22-46 thereof, or as disclosed in GB0723418.0, for example asdisclosed with reference to FIGS. 7-32 thereof, both of which priorpatent applications are incorporated herein by reference in theirentirety. The pump may be actuated by an actuator as disclosed in FIGS.1-6 of said GB0723418.0.

In one embodiment, there is provided an intranasal compositioncomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof. In another embodiment, such an intranasal composition isbenzalkonium chloride-free.

In another embodiment, there is provided an intranasal compositioncomprising a compound which isN-(4-{-4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide,or a pharmaceutically acceptable salt (such as a dihydrochloride salt)thereof. In another embodiment, such an intranasal composition isbenzalkonium chloride-free.

Inhaled administration involves topical administration to the lung, suchas by aerosol or dry powder composition.

Aerosol compositions suitable for inhaled administration may comprise asolution or fine suspension of the compound in a pharmaceuticallyacceptable aqueous or non-aqueous solvent. Aerosol compositions suitablefor inhalation can be either a suspension or a solution and generallycontain a compound of formula (I) or a pharmaceutically acceptable saltthereof and a suitable propellant such as a fluorocarbon orhydrogen-containing chlorofluorocarbon or mixtures thereof, such ashydrofluoroalkanes, e.g. 1,1,1,2-tetrafluoroethane,1,1,1,2,3,3,3-heptafluoro-n-propane or a mixture thereof. The aerosolcomposition may optionally contain additional excipients well known inthe art such as surfactants or co-solvents. Examples of surfactantsinclude, but are not limited to oleic acid, lecithin, an oligolacticacid or derivative e.g. as described in WO94/21229 and WO98/34596. Anexample of a co-solvent includes, but is not limited to ethanol. Aerosolcompositions may be presented in single or multidose quantities insterile form in a sealed container, which may take the form of acartridge or refill for use with an atomising device or inhaler.Alternatively, the sealed container may be a unitary dispensing devicesuch as a single dose nasal inhaler or an aerosol dispenser fitted witha metering valve (metered dose inhaler), which is intended for disposalonce the contents of the container have been exhausted.

Dry powder inhalable compositions may take the form of capsules andcartridges of, for example, gelatine, or blisters of, for example,laminated aluminium foil, for use in an inhaler or insufflator. Suchcompositions may be formulated comprising a powder mix of a compound offormula (I) or a pharmaceutically acceptable salt thereof and a suitablepowder base such as lactose or starch.

Optionally, for dry powder inhalable compositions, a compositionsuitable for inhaled administration may be incorporated into a pluralityof sealed dose containers (e.g. comprising the dry powder composition)mounted longitudinally in a strip or ribbon inside a suitable inhalationdevice. The container is rupturable or peel-openable on demand and thedose of e.g. the dry powder composition may be administered byinhalation via the device such as the DISKUST™ device, marketed byGlaxoSmithKline. The DISKUST™ inhalation device is for example describedin GB 2242134 A, and in such a device, at least one container for thecomposition in powder form (the container or containers may, forexample, be a plurality of sealed dose containers mounted longitudinallyin a strip or ribbon) is defined between two members peelably secured toone another; the device comprises: a means of defining an openingstation for the said container or containers; a means for peeling themembers apart at the opening station to open the container; and anoutlet, communicating with the opened container, through which a usercan inhale the composition in powder form from the opened container.

Aerosol compositions are typically arranged so that each metered dose or“puff” of aerosol contains about 20 μg-2000 μg, particularly about 20μg-500 μg of a compound of formula (I) or a pharmaceutically acceptablesalt thereof. Administration may be once daily or several times daily,for example 2, 3, 4 or 8 times, giving for example 1, 2 or 3 doses eachtime. The overall daily dose with an aerosol will be within the range ofabout 100₁4-10 mg, such as between about 200 μg-2000 μg. The overalldaily dose and the metered dose delivered by capsules and cartridges inan inhaler or insufflator will generally be double those with aerosolcompositions.

In another embodiment, there is provided a composition comprising acompound of formula (I) or a pharmaceutically acceptable salt thereofwhich is suitable for epicutaneous administration. An epicutaneouscomposition to be applied to the affected area e.g. the skin, by one ormore application per day, may be in the form of, for example, anointment, a cream, an emulsion, a lotion, a foam, a spray, an aqueousgel, or a microemulsion. Such compositions may optionally contain one ormore solubilising agents, skin-penetration-enhancing agents,surfactants, fragrances, preservatives or emulsifying agents.

Ointments, creams and gels, may, for example, be formulated with anaqueous or oily base with the addition of suitable thickening and/orgelling agent and/or solvents. Such bases may thus, for example, includewater and/or an oil such as liquid paraffin or a vegetable oil such asarachis oil or castor oil, or a solvent such as polyethylene glycol.Thickening agents and gelling agents which may be used according to thenature of the base include soft paraffin, aluminium stearate,cetostearyl alcohol, polyethylene glycols, woolfat, beeswax,carboxypolymethylene and cellulose derivatives, and/or glycerylmonostearate and/or non-ionic emulsifying agents. Lotions may beformulated with an aqueous or oily base and will in general also containone or more emulsifying agents, stabilising agents, dispersing agents,suspending agents or thickening agents.

In another embodiment, there is provided a composition comprising acompound of formula (I) or a pharmaceutically acceptable salt thereofwhich is suitable for ocular administration. Such compositions mayoptionally contain one or more suspending agents, one or morepreservatives, one or more wetting/lubricating agents and/or one or moreisotonicity adjusting agents. Examples of ophthalmic wetting/lubricatingagents may include cellulose derivatives, dextran 70, gelatin, liquidpolyols, polyvinyl alcohol and povidone such as cellulose derivativesand polyols.

In another embodiment, there is provided a composition comprising acompound which isN-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide,or a pharmaceutically acceptable salt (such as a dihydrochloride salt)thereof which is suitable for ocular administration.

In another embodiment, there is provided a composition comprising acompound of formula (I) or a pharmaceutically acceptable salt thereofwhich is suitable for oral administration. Tablets and capsules for oraladministration may be in unit dose form, and may contain conventionalexcipients, such as binding agents, fillers, tabletting lubricants,disintegrants and acceptable wetting agents. The tablets may be coatedaccording to methods well known in normal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspension, solutions, emulsions, syrups or elixirs, or may be inthe form of a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, emulsifying agents,non-aqueous vehicles (which may include edible oils), preservatives,and, if desired, conventional flavourings or colorants.

In another embodiment, there is provided a composition comprising acompound of formula (I) or a pharmaceutically acceptable salt thereofwhich is suitable for parenteral administration. Fluid unit dosage formssuitable for parenteral administration may be prepared utilising acompound of formula (I) or pharmaceutically acceptable salt thereof anda sterile vehicle which may be aqueous or oil based. The compound,depending on the vehicle and concentration used, may be either suspendedor dissolved in the vehicle. In preparing solutions, the compound may bedissolved for injection and filter sterilised before filling into asuitable vial or ampoule and sealing. Optionally, adjuvants such as alocal anaesthetic, preservatives and buffering agents may be dissolvedin the vehicle. To enhance the stability, the composition may be frozenafter filling into the vial and the water removed under vacuum. Thelyophilised parenteral composition may be reconstituted with a suitablesolvent just prior to administration. Parenteral suspensions may beprepared in substantially the same manner, except that the compound issuspended in the vehicle instead of being dissolved, and sterilisationcannot be accomplished by filtration. The compound may be sterilised byexposure to ethylene oxide before suspension in a sterile vehicle. Asurfactant or wetting agent may be included in the composition tofacilitate uniform distribution of the compound.

The compounds and pharmaceutical compositions according to the inventionmay also be used in combination with or include one or more (e.g. one ortwo) other therapeutic agents, for example other antihistaminic agentsfor example H4 or H3 receptor antagonists, anticholinergic agents,anti-inflammatory agents such as corticosteroids (e.g. fluticasonepropionate, fluticasone furoate, beclomethasone dipropionate, mometasonefuroate, triamcinolone acetonide, budesonide and the steroid disclosedin WO02/12265), non-steroidal anti-inflammatory drugs (NSAIDs) (e.g.sodium cromoglycate, nedocromil sodium), PDE-4 inhibitors, leukotrieneantagonists, lipoxygenase inhibitors, chemokine antagonists (e.g. CCR3,CCR1, CCR2, CCR4, CCR8, CXCR1, CXCR2), IKK antagonists, iNOS inhibitors,tryptase and elastase inhibitors, beta-2 integrin antagonists andadenosine 2a agonists; or beta adrenergic agents (e.g. salmeterol,salbutamol, formoterol, fenoterol, terbutaline, and the beta agonistsdescribed in WO 02/66422, WO 02/270490, WO02/076933, WO03/024439 andWO03/072539 and salts thereof); or antiinfective agents e.g. antibioticagents and antiviral agents.

It will be clear to a person skilled in the art that, where appropriate,the other therapeutic agent(s) may be used in the form of salts, (e.g.as alkali metal or amine salts or as acid addition salts), or prodrugs,or as esters (e.g. lower alkyl esters), or as solvates (e.g. hydrates)to optimise the activity and/or stability and/or physicalcharacteristics (e.g. solubility) of the therapeutic agent. It will beclear also that where appropriate, the therapeutic agents may be used inoptically pure form.

There is provided, in another embodiment, a combination comprising acompound of formula (I) or a pharmaceutically acceptable salt thereoftogether with one or more (such as one or two, e.g. one) othertherapeutically active agents, optionally with one or morepharmaceutically acceptable carriers and/or excipients.

In another embodiment, there is provided a combination comprising acompound which is6-butyl-8-({1-[3-(ethylsulfonyl)propyl]-4-piperidinyl}oxy)quinoline, ora pharmaceutically acceptable salt thereof, together with one or more(such as one or two, e.g. one) other therapeutically active agents (suchas those described herein), optionally with one or more pharmaceuticallyacceptable carriers and/or excipients.

In another embodiment, there is provided a combination comprising acompound which isN-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide,or a pharmaceutically acceptable salt (such as a dihydrochloride salt)thereof together with one or more (such as one or two, e.g. one) othertherapeutically active agents (such as those described herein),optionally with one or more pharmaceutically acceptable carriers and/orexcipients.

In another embodiment, there is provided a combination comprising acompound of formula (I) or a pharmaceutically acceptable salt thereofand an H3 and/or H4 antagonist.

Other histamine receptor antagonists which may be used alone, or incombination with an H1 receptor antagonist include antagonists (and/orinverse agonists) of the H4 receptor, for example, the compoundsdisclosed in Jablonowski et al., J. Med. Chem. 46:3957-3960 (2003), andantagonists (and/or inverse agonists) of the H3 receptor, for examplethe compounds described in WO2004/035556, the compounds described inWO2006/125665 and the compounds described in WO2006/090142.

In another embodiment, there is provided a combination comprising acompound of formula (I) or a pharmaceutically acceptable salt thereofand a β₂-adrenoreceptor agonist.

Examples of β₂-adrenoreceptor agonists include salmeterol (which may bea racemate or a single enantiomer, such as the R-enantiomer), salbutamol(which may be a racemate or a single enantiomer such as theR-enantiomer), formoterol (which may be a racemate or a singlediastereomer such as the R,R-diastereomer), salmefamol, fenoterol,carmoterol, etanterol, naminterol, clenbuterol, pirbuterol, flerbuterol,reproterol, bambuterol, indacaterol, terbutaline and salts thereof, forexample the xinafoate (1-hydroxy-2-naphthalenecarboxylate) salt ofsalmeterol, the sulfate salt or free base of salbutamol or the fumaratesalt of formoterol. In one embodiment, combinations containing acompound of formula (I) may include longer-acting β₂-adrenoreceptoragonists, for example, compounds which provide effective bronchodilationfor about 12 h or longer.

Other β₂-adrenoreceptor agonists include those described in WO02/066422, WO 02/070490, WO 02/076933, WO 03/024439, WO 03/072539, WO03/091204, WO 04/016578, WO 2004/022547, WO 2004/037807, WO 2004/037773,WO 2004/037768, WO 2004/039762, WO 2004/039766, WO01/42193 andWO03/042160.

Examples of β₂-adrenoreceptor agonists include:

-   3-(4-}[6-({(2R)-2-hydroxy-2,4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide;-   3-(3-}[7-({(2R)-2-hydroxy-2,4-hydroxy-3-hydroxymethyl)phenyl]ethyl}-amino)heptyl]oxy}propyl)benzenesulfonamide;-   4-{(1R)-2-[(6-(2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxyl    methyl)phenol;-   4-{(1R)-2-[(6-{4-[3-(cyclopentylsulfonyl)phenyl]butoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxylmethyl)phenol;-   N-[2-hydroxy]-5-[(1R)-1-hydroxy-2-[[2-4-[[(2R)-2-hydroxy-2-phenylethyl]amino]phenyl]ethyl]amino]ethyl]phenyl]formamide;-   N-2{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(8-hydroxy-2(1    H)-quinolinon-5-yl)ethylamine; and-   5-[(R)-2-(2-{4-[4-(2-amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one.

The β₂-adrenoreceptor agonist may be in the form of a salt formed with apharmaceutically acceptable acid selected from sulfuric, hydrochloric,fumaric, hydroxynaphthoic (for example. 1- or 3-hydroxy-2-naphthoic),cinnamic, substituted cinnamic, triphenylacetic, sutfamic, sulfanilic,naphthaleneacrylic, benzoic, 4-methoxybenzoic, 2- or 4-hydroxybenzoic,4-chlorobenzoic and 4-phenylbenzoic acid.

In another embodiment, there is provided a combination comprising acompound of formula (I) or a pharmaceutically acceptable salt thereofand an anti-inflammatory agent.

Anti-inflammatory agents include corticosteroids. Suitablecorticosteroids which may be used in combination with the compounds offormula (I) are those oral and inhaled corticosteroids and theirpro-drugs which have anti-inflammatory activity. Examples include methylprednisolone, prednisolone, dexamethasone, fluticasone propionate,6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-[(4-methyl-1,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester,6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-1,8-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester (fluticasone furoate),6α,9α-difluoro-1,6-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3S-yl) ester,6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3-tetramethycyclopropylcarbonyl)oxy-androsta-1,4-diene-17β-carbothioicacid S-cyanomethyl ester and6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-(1-methycyclopropylcarbonyl)oxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester, beclomethasone esters (for example the17-propionate ester or the 17,21-dipropionate ester), budesonide,flunisolide, mometasone esters (for example mometasone furoate),triamcinolone acetonide, rofleponide, ciclesonide(16α,17-[[(R)-cyclohexylmethylene]bis(oxy)]-11β,21-dihydroxy-pregna-1,4-diene-3,20-dione),butixocort propionate, RPR-106541, and ST-126. Corticosteroids ofparticular interest may include fluticasone propionate,6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-[(4-methyl-1,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester,6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester,6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3-tetramethycyclopropylcarbonyl)oxy-androsta-1,4-diene-17β-carbothioicacid S-cyano methylester,6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-(1-methycyclopropylcarbonyl)oxy-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl esterand mometasone furoate. In one embodiment the corticosteroid is6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester (fluticasone furoate) or mometasone furoate.

There is provided, in a further embodiment, a combination comprising acompound of formula (I) or a pharmaceutically acceptable salt thereof,together with a corticosteroid, such as fluticasone propionate or6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester (fluticasone furoate) or mometasone furoate.Such combinations may be of particular interest for intranasaladministration.

In another embodiment, there is provided a combination comprising acompound which isN-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide,or a pharmaceutically acceptable salt (such as a dihydrochloride salt)thereof together with6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester (fluticasone furoate). In another embodiment,the combination is suitable for intranasal administration.

In another embodiment, there is provided a combination comprising acompound of formula (I) or a pharmaceutically acceptable salt thereofand a glucocorticoid agonist.

Non-steroidal compounds having glucocorticoid agonism that may possessselectivity for transrepression over transactivation and that may beuseful in combination therapy include those covered in the followingpatent application and patents: WO03/082827, WO98/54159, WO04/005229,WO04/009017, WO04/018429, WO03/104195, WO03/082787, WO03/082280,WO03/059899, WO03/101932, WO02/02565, WO01/16128, WO00/66590,WO03/086294, WO04/026248, WO03/061651, WO03/08277, WO06/000401,WO06/000398 and WO06/015870.

Anti-inflammatory agents include non-steroidal anti-inflammatory drugs(NSAID's).

NSAID's include sodium cromoglycate, nedocromil sodium,phosphodiesterase (PDE) inhibitors (e.g. theophylline, PDE4 inhibitorsor mixed PDE3/PDE4 inhibitors), leukotriene antagonists, inhibitors ofleukotriene synthesis (eg. montelukast), iNOS (inducible nitric oxidesynthase) inhibitors (e.g. oral iNOS inhibitors), IKK antagonists,tryptase and elastase inhibitors, beta-2 integrin antagonists andadenosine receptor agonists or antagonists (e.g. adenosine 2a agonists),cytokine antagonists (e.g. chemokine antagonists, such as a CCR1, CCR2,CCR3, CCR4, or CCR8 antagonists) or inhibitors of cytokine synthesis, or5-lipoxygenase inhibitors. iNOS inhibitors include those disclosed inWO93/13055, WO98/30537, WO02/50021, WO95/34534 and WO99/62875.

In another embodiment there is provided the use of the compounds offormula (I) or a pharmaceutically acceptable salt thereof in combinationwith a phosphodiesterase 4 (PDE4) inhibitor. The PDE4-specific inhibitoruseful in this embodiment may be any compound that is known to inhibitthe PDE4 enzyme or which is discovered to act as a PDE4 inhibitor, andwhich are selective PDE4 inhibitors, not compounds which inhibit othermembers of the PDE family, such as PDE3 and PDE5, as well as PDE4.

Compounds which may be of interest includecis-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylicacid,2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-oneandcis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol].Also,cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylicacid (also known as cilomilast) and its salts, esters, pro-drugs orphysical forms, which is described in U.S. Pat. No. 5,552,438 issued 3Sep. 1996.

Other PDE4 inhibitors include AWD-12-281 from Elbion (Hofgen, N. et al.,15th EFMC Int. Symp. Med. Chem., (September 6-10, Edinburgh) 1998, Abst.P. 98; CAS reference No. 247584020-9); a 9-benzyladenine derivativenominated NCS-613 (INSERM); D-4418 from Chiroscience andSchering-Plough; a benzodiazepine PDE4 inhibitor identified as CI-1018(PD-168787) and attributed to Pfizer; a benzodioxole derivativedisclosed by Kyowa Hakko in WO99/16766; K-34 from Kyowa Hakko; V-11294Afrom Napp (Landells, L. J. et al., Eur. Resp. J. [Ann. Cong. Eur. Resp.Soc. (September 19-23, Geneva) 1998] 1998, 12 (Suppl. 28): Abst P2393);roflumilast (CAS reference No 162401-32-3) and a pthalazinone(WO99/47505) from Byk-Gulden; Pumafentrine,(−)-p-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[c][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide which is a mixed PDE3/PDE4inhibitor which has been prepared and published on by Byk-Gulden, nowAltana; arofylline under development by Almirall-Prodesfarma;VM554/UM565 from Vernalis; or T-440 (Tanabe Seiyaku; Fuji, K. et al., J.Pharmacol. Exp. Ther., 284(1):162, (1998)), and T2585.

Further PDE4 inhibitors which may be of interest are disclosed in thepublished international patent applications WO04/024728 (Glaxo GroupLtd), WO04/056823 (Glaxo Group Ltd) and WO04/103998 (Glaxo Group Ltd). Aparticular compound of interest is6-({3-[(dimethylamino)carbonyl]phenyl}sulfonyl)-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamideor a pharmaceutically acceptable salt thereof, which is described inInternational Patent Application WO04/103998.

In another embodiment, there is provided a combination comprising acompound which isN-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-pipendinyl}butyl)ethanesulfonamide,or a pharmaceutically acceptable salt (such as a dihydrochloride salt)thereof together with6-({3-[(dimethylamino)carbonyl]phenyl}sulfonyl)-8-methyl-4-{[3-(methyloxy)phenyl]amino]-3-quinolinecarboxamideor a pharmaceutically acceptable salt thereof.

In another embodiment, there is provided a combination comprising acompound of formula (I) or a pharmaceutically acceptable salt thereofand an anticholinergic agent.

Anticholinergic agents are those compounds that act as antagonists atthe muscarinic receptors, in particular those compounds which areantagonists of the M₁ or M₃ receptors, dual antagonists of the M₁/M₃ orM₂/M₃, receptors or pan-antagonists of the M₁/M₂/M₃ receptors. Exemplarycompounds for administration via inhalation include ipratropium (forexample, as the bromide, CAS 22254-24-6, sold under the name Atrovent),oxitropium (for example, as the bromide, CAS 30286-75-0) and tiotropium(for example, as the bromide, CAS 136310-93-5, sold under the nameSpiriva). Also of interest are revatropate (for example, as thehydrobromide, CAS 262586-79-8) and LAS-34273 which is disclosed inWO01/04118. Exemplary compounds for oral administration includepirenzepine (for example, CAS 28797-61-7), darifenacin (for example, CAS133099-04-4, or CAS 133099-07-7 for the hydrobromide sold under the nameEnablex), oxybutynin (for example, CAS 5633-20-5, sold under the nameDitropan), terodiline (for example, CAS 15793-40-5), tolterodine (forexample, CAS 124937-51-5, or CAS 124937-52-6 for the tartrate, soldunder the name Detrol), otilonium (for example, as the bromide, CAS26095-59-0, sold under the name Spasmomen), trospium chloride (forexample, CAS 10405-02-4) and solifenacin (for example, CAS 242478-37-1,or CAS 242478-38-2, or the succinate also known as YM-905 and sold underthe name Vesicare).

Other anticholinergic agents include compounds which are disclosed inU.S. patent application 60/487,981, published as WO2005/009439 and thosecompounds disclosed in U.S. patent application 60/511,009, published asWO2005/037280.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical composition and thus the presentinvention further provides pharmaceutical compositions comprising acombination as defined above optionally together with a pharmaceuticallyacceptable carrier and/or excipient.

The individual compounds of such combinations may be administered eithersequentially in separate pharmaceutical compositions or simultaneouslyin combined pharmaceutical compositions. Appropriate doses of knowntherapeutic agents will be readily appreciated by those skilled in theart.

Compounds of formula (I) may be prepared by the methods described belowor by similar methods. Thus the following Intermediates and Examplesillustrate the preparation of the compounds of formula (I), and are notto be considered as limiting the scope of the disclosure in any way.

General Experimental Abbreviations

-   DCM: Dichloromethane-   DMF: N,N′-Dimethyl formamide-   EtOAc: Ethyl acetate-   g: Grams-   h: Hours-   HPLC: High performance liquid chromatography-   HRMS: High-resolution mass-spectroscopy-   LCMS: Liquid-chromatography mass-spectroscopy-   MDAP: Mass-directed auto-preparative HPLC-   min Minutes-   mg: Milligrams-   ml: Millilitres-   NMP: N-methylpyrrolidinone-   s.g.: specific gravity (gml⁻¹)-   THF: Tetrahydrofuran

General Experimental Procedures

Flash silica gel refers to Merck Art No. 9385; silica gel refers toMerck Art No. 7734.

SCX cartridges are Ion Exchange SPE columns where the stationary phaseis polymeric benzene sulfonic acid. These are used to isolate amines.

SCX2 cartridges are Ion Exchange SPE columns where the stationary phaseis polymeric propylsulfonic acid. These are used to isolate amines.

LCMS was conducted on a Supelcosil LCABZ+PLUS column (3.3 cm×4.6 mm ID)eluting with 0.1% formic acid and 0.01 M ammonium acetate in water(solvent A) and 0.05% formic acid 5% water in MeCN (solvent B), usingthe following elution gradient 0.0-7 min 0% B, 0.7-4.2 min 100% B,4.2-5.3 min 0% B, 5.3-5.5 min 0% B at a flow rate of 3 mlmin⁻¹. The massspectra were recorded on a Fisons VG Platform spectrometer usingelectrospray positive and negative mode (ES+ve and ES−ve).

The Flashmaster II is an automated multi-user flash chromatographysystem, available from Argonaut Technologies Ltd, which utilisesdisposable, normal phase, SPE cartridges (2 g to 100 g). It providesquaternary on-line solvent mixing to enable gradient methods to be run.Samples are queued using the multi-functional open access software,which manages solvents, flow-rates, gradient profile and collectionconditions. The system is equipped with a Knauer variable wavelengthUV-detector and two Gilson FC204 fraction-collectors enabling automatedpeak cutting, collection and tracking.

Mass directed autopreparative (MDAP) HPLC was conducted on a WatersFractionLynx system comprising of a Waters 600 pump with extended pumpheads, Waters 2700 autosampler, Waters 996 diode array and Gilson 202fraction collector on a 10 cm×2.54 cm internal diameter ABZ+column,eluting with 0.1% formic acid in water (solvent A) and 0.1% formic acidin MeCN (solvent B), using an appropriate elution gradient over 15 minat a flow rate of 20 mlmin⁻¹ and detecting at 200-320 nm at roomtemperature. Mass spectra were recorded on Micromass ZMD massspectrometer using electro spray positive and negative mode, alternatescans. The software used was MassLynx 3.5 with OpenLynx and FractionLynxoptions.

The ¹H NMR spectra were recorded on a Bruker AV400 operating at 400 MHz.Standard deuterated solvents were used. Tetramethylsilane may have beenused as internal standard.

Reactions are routinely monitored by methods well known to those skilledin the art, such as TLC, LCMS and/or HPLC. Such methods are used toassess whether a reaction has gone to completion, and reaction times maybe varied accordingly.

The XRPD method which was employed to analyse crystalline forms ofcompounds was as follows:

Manufacturer PANalytical-The Netherlands Instrument X′Pert ProDiffractometer Type DY1850 Tube anode Cu K-Alpha1 wavelength (A °) 1.54056 K-Alpha2 wavelength (A °)  1.54439 Ration Alpha 1:2  0.50000Divergence slit Prog.Div.Slit Receiving slit Prog.Rec.Slit Generatorvoltage (kV) 40 Tube Current (mA) 45 Detector X′celerator Data Anglerange (°2θ)  2.000-39.997 Scan type Continuous Scan step size  0.0167Scan step time (seconds) 31.75 Sample preparation Backfilled

XRPD analysis was performed on a PANalytical X′Pert Pro X-ray powderdiffractometer, model X′ Pert Pro PW3040/60, serial number DY1850 usingan X′Celerator detector. The acquisition conditions were: radiation: CuK, generator tension: 40 kV, generator current: 45 mA, start angle:2.000° 20, end angle: 39.997 °2θ, step size: 0.0167, time per step:31.75 seconds. The sample was prepared by backfilling. The margin oferror is approximately ±0.1 °2θ for each of the peak assignments.

Compounds were named using ACD/Name PRO6.02 chemical naming softwarefrom Advanced Chemistry Developments Inc.; Toronto, Ontario, M5H2L3,Canada.

INTERMEDIATES Intermediate 1 6-Bromo-8-fluoroquinoline

A solution of concentrated sulphuric acid (63 ml, 820 mmol) in water(49.4 ml) was treated with sodium 3-nitro-benzenesulfonate (commerciallyavailable, for example, from Aldrich) (47.9 g, 213 mmol) and glycerol(commercially available, for example, from Fluka and/or Aldrich) (52 ml,720 mmol) to give a thick grey suspension. This was heated to 110° C.(internal temperature was 85° C.). 4-Bromo-2-fluoroaniline (commerciallyavailable, for example, from Fluorochem and/or Aldrich) (38 g, 200 mmol)was added over 10 min in portions, during which the internal temperaturerose to 95° C. The reaction was heated to 140° C. (internal temperaturewas 133° C.) and stirred overnight. The reaction mixture was cooled andthen poured into water (1000 ml) and basified to pH 7 with aqueousammonia (0.88 s.g, approximately 190 ml). The brown precipitate thatformed was collected by filtration and partially dried. This solid (63g) was loaded onto a column of silica (1500 ml) and eluted with EtOAc togive the title compound as a light brown solid (43.8 g, 97%). LCMSRT=2.87 min, ES+ve rrriz 226/228 [M+H]⁺.

Intermediate 2 6-Butyl-8-fluoroquinoline

A mixture of 6-bromo-8-fluoroquinoline (for example, as prepared forIntermediate 1) (24 g, 106 mmol) in DMF (150 ml) was treated undernitrogen with potassium carbonate (33 g, 240 mmol), tributylboranesolution in THF (commercially available, for example, from Aldrich) (1M,200 ml) and [1,1′-bis(diphenylphosphino) ferrocene palladium (II)]chloride (1 g, 1.2 mmol). The resulting mixture was stirred undernitrogen and heated at 75° C. overnight. The mixture was allowed tocool, diluted with water and extracted with EtOAc (×3). The combinedorganic layers were filtered through a frit to remove any insolublematerial and the filtrate washed with water. The organic layer was dried(MgSO₄), and the filtrate evaporated to dryness. The residue waspurified twice by flash chromatography eluting with DCM-EtOAc (1:0 to2:1) to afford the title compound (14.47 g, 67%). LCMS RT=3.38 min,ES+ve m/z 204 [M+H]⁺.

Intermediate 3 1,1-Dimethylethyl4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinecarboxylate

A solution of 6-butyl-8-fluoroquinoline (for example, as prepared forIntermediate 2) (14.4 g, 70.9 mmol) in NMP (20 ml) was added to amixture of tert-butyl-4-hydroxy-1-piperidinecarboxylate (commerciallyavailable, for example, from Aldrich) (21.6 g, 108 mmol) and sodiumtert-butoxide (10.4 g, 108 mmol) in NMP (75 ml), and the resultingmixture was stirred at 140° C. for approximately 90 min and then allowedto cool overnight. The reaction mixture was treated with ammoniumchloride solution and extracted with EtOAc (×2). The combined organicextracts were washed with water, dried (MgSO₄), filtered and evaporatedto dryness. The residue was purified by flash chromatography elutingwith DCM-EtOAc (1:0 to 1:1) and then twice by Flashmaster chromatographyeluting with DCM-EtOAc (1:0 to 3:1) over 40 min to give the titlecompound (22 g). LCMS RT=3.49 min, ES+ve tri/z 385 [M+H]⁺

Intermediate 4 6-Butyl-8-(4-piperidinyloxy) quinoline

1,1-Dimethylethyl 4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinecarboxylate(for example, as prepared for Intermediate 3) (21.5 g, 56 mmol) wasdissolved in DCM (50 ml) and trifluoroacetic acid (50 ml) was added veryslowly. The mixture was stirred at room temperature for 1 h. The solventwas evaporated to dryness and the residue treated with saturated aqueoussodium carbonate solution. The mixture was extracted with EtOAc (×2),washed with water, and dried (MgSO₄). The drying agent was removed byfiltration and the filtrate was evaporated to dryness (22 g). This wasstill a trifluoracetic acid salt and was re-dissolved in EtOAc, washedwith aqueous sodium carbonate, water, and dried (MgSO₄). The dryingagent was removed by filtration and the filtrate was evaporated todryness to afford the title compound (15.9 g). LCMS RT=2.45 min, ES+vem/z 285 [M+H]⁺.

Intermediate 5 6-Chloro-8-fluoroquinoline

A solution of concentrated sulphuric acid (16 ml, 300 mmol) in water (12ml) was treated with sodium 3-nitro-benzenesulfonate (commerciallyavailable, for example, from Aldrich) (11.3 g, 50 mmol) and glycerol(commercially available, for example, from Fisher and/or Aldrich) (12ml, 160 mmol) to give a suspension. This was heated to 110° C. withstirring, and 4-chloro-2-fluoroaniline (commercially available, forexample, from Aldrich) (5.6 ml, 50 mmol) was added. The reaction washeated to 140° C. and stirred overnight. The reaction mixture was cooledand then poured into water (400 ml) and basified to pH 11 with aqueousammonium hydroxide (0.88 s.g., 60 ml). The brown precipitate that formedwas collected by filtration and dried under suction. EtOAc was thenadded to the sinter funnel, dissolving most of the material to give abrown solution. This filtrate was concentrated in vacuo to give a brownsolid (7.7 g). This was purified by chromatography on silica (2×100 g,eluting with 0-50% EtOAc-cyclohexane over 60 min). The relevantfractions were concentrated in vacuo to give the title compound as ayellow solid (6.5 g, 70%) LCMS RT=2.78 min, ES+ve m/z 182/184 [M+H]⁺.

Intermediate 6 1,1-Dimethylethyl4-[(6-chloro-8-quinolinyl)oxy]-1-piperidinecarboxylate

6-Chloro-8-fluoroquinoline (for example, as prepared for Intermediate 5)(2.18 g, 12 mmol) was dissolved in NMP (20 ml) and treated with1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate (commerciallyavailable, for example, from Acros and/or Aldrich) (4.85 g, 24 mmol) andsodium tert-butoxide (2.38 g, 25 mmol). Further NMP was added (5 ml) andthe resulting mixture was stirred at 140° C. for 1 h, and then allowedto cool overnight. The reaction mixture was treated with water andextracted with toluene. The organic extract was washed with water (×3),dried (MgSO₄), and concentrated in vacuo. The residue was purified bysilica chromatography (2×70 g), eluting with 0-100% EtOAc-cyclohexaneover 30 min. The relevant fractions were concentrated in vacuo to givethe title compound as a yellow gum (2.73 g, 63%): LCMS RT=3.37 min,ES+ve m/z 363/365 [M+H]⁺.

Intermediate 7 1,1-Dimethylethyl4-[(6-pentyl-8-quinolinyl)oxy]-1-piperidinecarboxylate

1,1-Dimethylethyl 4-[(6-chloro-8-quinolinyl)oxy]-1-piperidinecarboxylate(for example, as prepared for Intermediate 6) (2.73 g, 7.5 mmol) wasdissolved in a mixture of THF (55 ml), NMP (5.6 ml) and iron (III)acetylacetonate (220 mg, 0.62 mmol) were added, and the mixture wascooled to 0° C. and stirred under a nitrogen atmosphere. n-Pentylmagnesium bromide (commercially available, for example, from TCI-Europeand/or Aldrich) was added dropwise over 9 min. The stirring wascontinued at 0° C. for 1 h, and the reaction was then allowed to warm toroom temperature with stirring overnight. The reaction mixture wastreated with aqueous ammonium chloride solution and extracted with EtOAc(×3). The combined organic extracts were filtered, dried (MgSO₄), andconcentrated in vacuo. The residue was purified by silica chromatography(2×100 g), eluting with 0-50% EtOAc-cyclohexane over 40 min. Therelevant fractions were concentrated in vacuo to give the title compoundas a yellow oil (2.2 g, 74%): LCMS RT=3.76 min, ES+ve m/z 399 [M+H]⁺.

Intermediate 8 6-Pentyl-8-(4-piperidinyloxy)quinoline

1,1-Dimethylethyl 4-[(6-pentyl-8-quinolinyl)oxy]-1-piperidinecarboxylate(for example, as prepared for Intermediate 7) (2.20 g, 5.52 mmol) wasdissolved in dioxane (10 ml) and the solution was treated with asolution of hydrogen chloride in dioxane (4M, 12.5 ml). The mixture wasstirred under nitrogen overnight at room temperature, and thenconcentrated in vacuo. The residue was applied to a SCX-2 ion exchangecartridge (70 g) which had been preconditioned with methanol. Thecartridge was washed with methanol, and then eluted with 10% aqueous0.88 s.g. ammonia in methanol. The relevant basic fractions wereconcentrated in vacuo to give the title compound (1.88 g); LCMS RT=2.70min, ES+ve m/z 299 [M+H]⁺.

Intermediate 9 1,1-Dimethylethyl(3R)-3-[(6-butyl-8-quinolinyl)oxy]-1-pyrrolidinecarboxylate

This was prepared in an analogous manner to Intermediate 3, using6-butyl-8-fluoroquinoline (for example, as prepared for Intermediate 2)and N-tert-butoxycarbonyl-(R)-(−)-3-pyrrolidinol (commerciallyavailable, for example, from Aldrich) instead of 1,1-dimethylethyl4-hydroxy-1-piperidinecarboxylate. The reaction time was 3 h instead of1.5 h. LCMS RT=3.56 min, ES+ve m/z 371 (M+H)⁺.

Intermediate 10 6-Butyl-8-[(3R)-3-pyrrolidinyloxy]quinoline

This was prepared in an analogous manner to Intermediate 4, using1,1-dimethylethyl(3R)-3-[(6-butyl-8-quinolinyl)oxy]-1-pyrrolidinecarboxylate (forexample, as prepared for Intermediate 9) and 4 M hydrogen chloride in1,4-dioxane instead of trifluoroacetic acid for 45 min. LCMS RT=2.46min, ES+ve m/z 271 (M+H)⁺.

Intermediate 11 2-[(1,1-Dimethylethyl)thio]ethanol

A mixture of bromoethanol (commercially available, for example, fromAvocado) (1.5 ml, 21 mmol) and sodium 2-methyl-2-propanethiolate(commercially available, for example, from Aldrich) (2.5 g, 22 mmol) inDMF (10 ml) were heated to 70° C. overnight. The mixture was cooled toroom temperature, diluted with water and extracted with EtOAc (×2). Theorganic solution was washed with water, brine, dried (MgSO₄), andevaporated under reduced pressure to give a mixture containing startingmaterial and product by NMR (578 mg). This was re-dissolved in DMF (5ml) and treated with sodium 2-methyl-2-propanethiolate (2.5 g, 22 mmol)and heated to 80° C. for 4 days. The mixture was cooled to roomtemperature, diluted with water and extracted with EtOAc (×2). Theorganic solution was washed with water (×5), brine, dried (MgSO₄), andevaporated under reduced pressure to give the title compound (332 mg,9%): ¹H NMR δ (CDCl₃) 3.73 (2H, t, J=6 Hz), 2.77 (2H, t, J=6 Hz),2.19-2.07 (1H, br), 1.31 (9H, s).

Intermediate 12 2-Chloroethyl 1,1-dimethylethyl sulfide

A solution of 2-[(1,1-dimethylethyl)thio]ethanol (for example, asprepared for Intermediate 11) in DCM (5 ml) was treated withtriethylamine (1 ml, 7 mmol), followed by methanesulfonyl chloride(commercially available, for example, from Aldrich) (0.38 ml, 5 mmol) atroom temperature. After 1 h the mixture was diluted with DCM and washedwith water (×3), 2 M hydrochloric acid, water, dried (MgSO₄), andevaporated under reduced pressure to give the title compound (354 mg,94%): ¹H NMR δ (CDCl₃) 3.61 (2H, dd, J=8, 7 Hz), 2.88 (2H, dd, J=8, 7Hz), 1.31 (9H, s).

Intermediate 13 2-Chloroethyl 1,1-dimethylethyl sulfone

A solution of 2-chloroethyl 1,1-dimethylethyl sulfide (for example, asprepared for Intermediate 12) (354 mg, 2.31 mmol) in DCM (10 ml) wastreated with m-chloroperbenzoic acid (commercially available, forexample, from Aldrich) (1.5 g, 57-86% pure, at least 5 mmol) and themixture was stirred at room temperature for 2 h. The mixture was dilutedwith DCM and washed with water, sodium metabisulfite solution, sodiumbicarbonate solution, dried (MgSO₄), and evaporated under reducedpressure to give the title compound (208 mg, 49%): ¹H NMR δ (CDCl₃) 3.95(2H, dd, J=8, 7 Hz), 3.38 (2H, dd, J=8, 7 Hz), 1.42 (9H, s).

Intermediate 14 3-Chloropropyl ethyl sulfone

Sodium ethanethiolate (commercially available, for example, fromAldrich) (2.0 g, 24 mmol) in ethanol (24 ml) was treated with1-bromo-3-chloropropane (commercially available, for example, fromAldrich) (2.35 ml, 24 mmol) and the mixture was stirred at roomtemperature for 3 days. The mixture was then diluted with diethyl etherand filtered to remove the white precipitate. The filtrate was thenconcentrated by distillation of the solvents at atmospheric pressure.The solid residue from the filtration was combined with the solidresidue from the distillation, and partitioned between water and DCM.The aqueous phase was extracted with DCM and the combined organicsolutions were dried (MgSO₄), filtered, and the filtrate was treatedwith m-chloroperbenzoic acid (commercially available, for example, fromAldrich) (1 g, 57-86% pure, at least 3 mmol) and the mixture was stirredat room temperature overnight. The reaction mixture was diluted with DCMand washed with sodium bicarbonate solution. The organic solution waswashed with aqueous sodium metabisulfite solution (×2), aqueous sodiumbicarbonate solution, dried (MgSO₄) and evaporated under reducedpressure. The residue (790 mg) was dissolved in DCM and applied to asilica cartridge (20 g) eluting with a gradient ofdiethylether-petroleum ether (40-60° C.) (20%-60%) to give the titlecompound (260 mg, 6%): ¹H NMR δ (CDCl₃) 3.71 (2H, t, J=7 Hz), 3.15 (2H,t, J=7 Hz), 3.04 (2H, q, J=7 Hz), 2.40-2.30 (2H, m), 1.44 (3H, t, J=7Hz).

Intermediate 15 3-(Ethylthio)propyl 4-methylbenzenesulfonate PreparationA:

A solution of 3-(ethylthio)propanol (commercially available, forexample, from Alfa Aesar) (1.2 g, 10 mmol) in pyridine (10 ml) wastreated portionwise with p-toluenesulfonyl chloride (commerciallyavailable, for example from Aldrich) (1.9 g, 10 mmol) at roomtemperature and the solution was stirred for 20 h. The reaction mixturewas diluted with EtOAc, washed with water, 2 M hydrochloric acid, sodiumbicarbonate solution (×2), brine, dried (MgSO₄), and evaporated underreduced pressure. The residue (1.2 g) was purified by Flashmaster 2chromatography on a silica cartridge (70 g) eluting with 0 to 25%EtOAc-cyclohexane over 40 min. The appropriate fractions were combinedand evaporated to give the title compound (667 mg, 24%): LCMS RT=3.37min, ES+ve m/z 275 (M+H)⁺.

Preparation B:

Sodium ethanethiolate (commercially available, for example from Aldrich)(840 mg, 10 mmol) was added portionwise over 10 min to a solution of1,3-propanediol ditosylate (commercially available, for example, fromAldrich) (3.84 g, 10 mmol) in DMF (25 ml) at room temperature undernitrogen and the mixture was stirred for 3 days and then heated to 75°C. for 4 h. The solvent was removed under reduced pressure and theresidue was partitioned between EtOAc and aqueous sodium bicarbonate.The organic solution was washed with aqueous sodium bicarbonate, dried(MgSO₄) and evaporated under reduced pressure. The residue (1.9 g) wasdissolved in DCM and purified by Flashmaster 2 chromatography on asilica cartridge (70 g) eluting with 0-25% EtOAc-cyclohexane over 40 minto give the title compound (250 mg, 9%): ¹H NMR δ (CDCl₃) 7.80 (2H, d,J=8 Hz), 7.36 (2H, d, J=8 Hz), 4.15 (2H, t, J=6 Hz), 2.54 (2H, t, J=7Hz), 2.48 (2H, q, J=7 Hz), 2.46 (3H, s), 1.97-1.88 (2H, m), 1.21 (3H, t,J=7 Hz).

Intermediate 16 3-(Ethylsulfonyl)propyl 4-methyl benzenesulfonate

A solution of 3-(ethylthio)propyl 4-methylbenzenesulfonate (for example,as prepared for Intermediate 15) (2.43 mmol) in DCM (40 ml) was treatedwith m-chloroperbenzoic acid (commercially available, for example, fromAldrich) (1.9 g, 57-86% pure, at least 6.6 mmol) and the mixture wasstirred at room temperature for 2.5 h. The reaction mixture was dilutedwith DCM and washed with aqueous solution of sodium bicarbonate, sodiummetabisulfite, water, dried (MgSO₄), and concentrated under reducedpressure to give the title compound, which solidified on standing (735mg, 99%): ¹H NMR δ (CDCl₃) 7.80 (2H, d, J=8 Hz), 7.37 (2H, d, J=8 Hz),4.18 (2H, t, J=6 Hz), 3.04 (2H, t, J=7 Hz), 3.00 (2H, q, J=7 Hz), 2.47(3H, s), 2.26-2.19 (2H, m), 1.40 (3H, t, J=7 Hz).

Intermediate 17 3-Bromopropyl 1,1-dimethylethyl sulfone and3-chloropropyl 1,1-dimethylethyl sulfone

A solution of 1-bromo-3-chloropropane (commercially available, forexample, from Aldrich) (4.0 ml, 40 mmol) in DMF (5 ml) was treated withsodium 2-methyl-2-propanethiolate (commercially available, for example,from Aldrich) (3.36 g, 30 mmol) and the mixture was stirred for 24 h atroom temperature and another 24 h at 70° C. The mixture was allowed tocool to room temperature, and partitioned between water and diethylether. The aqueous layer was again extracted with diethyl ether and thecombined organic solutions were washed with water (×4), brine (×2),dried (MgSO₄) and evaporated under reduced pressure to give an oil (4.3g) which solidified on standing at room temperature. This was dissolvedin DCM (80 ml) and treated with m-chloroperbenzoic acid (commerciallyavailable, for example, from Aldrich) (13.8 g, 57-86% pure, at least 48mmol) and the mixture was stirred overnight at room temperature. Themixture was diluted with DCM and washed with aqueous sodium bicarbonatesolution (×2), 1 M sodium hydroxide (100 ml), dried (MgSO₄), andevaporated. The residue (4.85 g) was split into two portions; oneportion (1.8 g) was purified by Flashmaster 2 chromatography on a silicacartridge (100 g) eluting with 0-50% EtOAc-cyclohexane over 40 min. Theremainder was purified by flash chromatography on silica (150 g) elutingwith 0-50% EtOAc-cyclohexane. Appropriate fractions were combined andevaporated to give a mixture of the title compounds (1.1 g) in a 1:1ratio: ¹H NMR δ (CDCl₃) 3.75 (2H, t, J=6 Hz), 3.11 (2H, t, J=7 Hz),2.43-2.36 (2H, m), 1.45 (9H, s) for the chloride and 3.61 (2H, t, J=6Hz), 3.11 (2H, t, J=7 Hz), 2.51-2.44 (2H, m), 1.45 (9H, s) for thebromide.

Intermediates 18 to 20 were prepared in an analogous manner to thatdisclosed for Intermediate 17:

Intermediate 18 3-Bromopropyl propyl sulfone and 3-chloropropyl propylsulfone

Obtained as a mixture of the title compounds using sodium1-propanethiolate (commercially available, for example, from Aldrich)instead of sodium2-methyl-2-propanethiolate (ratio: 4:3bromide:chloride): ¹H NMR δ (CDCl₃) includes 3.70 (2H, t, J=6 Hz,minor), 3.55 (2H, t, J=6 Hz, major), 3.20-3.10 (4H, m), 1.93-1.82 (2H,m), 1.09 (3H, t, J=7 Hz).

Intermediate 19 3-Bromopropyl methyl sulfone and 3-chloropropyl methylsulfone

Obtained as a mixture of the title compounds using sodiummethanethiolate (commercially available, for example, from Aldrich)instead of sodium 2-methyl-2-propanethiolate (ratio: 64:36,bromide:chloride): LCMS RT=0.86 min, ES+ve m/z 174/176 (3:1, M+NH₄)⁺ andRT=1.00 min, ES+ve m/z 218/220 [(1:1), (M+NH₄)⁺].

Intermediate 20 3-Bromopropyl 1-methylethyl sulfone and 3-chloropropyl1-methylethyl sulfone

Obtained as a mixture of the title compounds using sodium2-propanethiolate (commercially available, for example, from Aldrich)instead of sodium 2-methyl-2-propanethiolate (ratio: 43:57,chloride:bromide) ¹H NMR δ (CDCl₃) 3.71 (2H, t, J=6 Hz, minor), 3.56(2H, t, J=6 Hz, major), 3.16-3.09 (3H, m), 2.45-2.30 (2H, m), 1.41 (6H,d, J=7 Hz).

Intermediate 21 4-Bromobutyl 1,1-dimethylethyl sulfide

A solution of 1,4-dibromobutane (commercially available, for example,from Aldrich) (4.7 ml, 40 mmol) in DMF (10 ml) was treated with sodium2-methyl-2-propanethiolate (commercially available, for example, fromAldrich) (3.36 g, 30 mmol) and the mixture was heated for 23 h at 70° C.The mixture was allowed to cool to room temperature, and partitionedbetween water and EtOAc. The organic solution was washed with water(×4), aqueous sodium bicarbonate solution, brine, dried (MgSO₄), andevaporated. The residue was purified by flash column chromatography onsilica (200 g) eluting with 0-50% EtOAc-cyclohexane to give the titlecompound (1.4 g, 21%): ¹H NMR δ (CDCl₃) 3.46 (2H, t, J=7 Hz), 2.96 (2H,t, J=7 Hz), 2.15-2.03 (4H, m), 1.44 (9H, s).

Intermediate 22 4-Bromobutyl 1,1-dimethylethyl sulfone

A solution of 4-bromobutyl 1,1-dimethylethyl sulfide (for example, asprepared for Intermediate 21) (1.4 g, 6.2 mmol) in DCM (15 ml) wastreated with m-chloroperbenzoic acid (commercially available, forexample, from Aldrich) (4.5 g, 60% pure, 16 mmol) and the mixture wasstirred at room temperature overnight. The mixture was diluted with DCMand washed with aqueous sodium bicarbonate solution (×4), water, dried(MgSO₄), and evaporated under reduced pressure to give the titlecompound contaminated with m-chloroperbenzoic acid. The mixture wasdissolved in EtOAc and washed with aqueous sodium bicarbonate solution(×4), 2 M sodium hydroxide, dried (MgSO₄), and evaporated under reducedpressure to give the title compound (1.14 g, 71%) as a solid: LCMSRT=2.68 min, ES+ve m/z 274/276 [(1:1), (M+NH₄)⁺].

Intermediate 23 3-(Cyclopentylthio)-1-propanol

To a suspension of sodium hydride (commercially available, for example,from Aldrich) (60% dispersion in mineral oil; 800 mg, 20 mmol) in dryDMF (30 ml) was carefully added cyclopentyl mercaptan (commerciallyavailable, for example, from Aldrich and/or Alfa Aesar) (2.14 ml, 20mmol). The resultant suspension was stirred at room temperature, undernitrogen for 15 min before adding 3-bromopropanol (commerciallyavailable, for example, from Aldrich) (1.81 ml, 20 mmol). The mixturewas then stirred under nitrogen and heated to 80° C. overnight. Water(20 ml) was cautiously added to the reaction mixture, followed bydiethyl ether (50 ml). The aqueous solution was extracted with diethylether (2×50 ml). The combined organic solutions were washed with water(100 ml) and brine (100 ml) and concentrated in vacuo to leave a yellowoil, which was purified by flash chromatography on silica eluting withcyclohexane-EtOAc (3:1) increasing to (1:1). The solvents were removedin vacuo to afford the title compound (2.18 g). LCMS RT=2.61 min, ES+vem/z 161 (M+H)⁺.

Intermediate 24 3-(Cyclopentylthio)propyl methanesulfonate

To a solution of 3-(cyclopentylthio)-1-propanol (for example, asprepared for Intermediate 23) (1.05 g, 6.56 mmol) in dry DCM (5 ml) wasadded diisopropylethylamine (1.37 ml, 7.87 mmol), and thenmethanesulfonyl chloride (commercially available, for example, fromAldrich) (0.609 ml, 7.87 mmol) at 20° C. The reaction mixture wasstirred at room temperature, under nitrogen for 2.5 h and then dilutedwith DCM (10 ml) and saturated sodium bicarbonate solution (20 ml). Thephases were separated using a hydrophobic frit. The organic phase wasconcentrated in vacuo to afford the title compound (1.74 g): LCMSRT=3.13 min, ES+ve rri/z 239 (M+H)⁺.

Intermediate 25 3-(Cyclopentylsulfonyl)propyl methanesulfonate

To a solution of 3-(cyclopentylthio)propyl methanesulfonate (forexample, as prepared for Intermediate 24) (1.7 g, 6.54 mmol) in DCM (10ml) was added m-chloroperbenzoic acid

(commercially available, for example, from Aldrich) (57-86% pure; 4.46g, at least 15 mmol). The mixture was stirred at room temperature forabout 4 h and then left to stand overnight. The reaction mixture wasthen diluted with DCM (25 ml) and washed with 2 M sodium metabisulfitesolution (×2). The organic solution was then washed with saturatedsodium bicarbonate solution (×3), 2 M sodium sulfite (2×100 ml), water(100 ml) and brine (100 ml) and then concentrated in vacuo to afford thetitle compound (1.8 g). LCMS RT=2.13 min, ES+ve m/z 288 (M+H)⁺.

Intermediate 26 Ethyl 3-(ethylthio)butanoate

Ethyl crotonate (commercially available, for example, from Aldrich)(2.37 g, 20.8 mmol) was dissolved in DMF (60 ml) and stirred at roomtemperature. Sodium ethanethiolate (commercially available, for example,from Aldrich) (1.66 g, 19.7 mmol) was added portionwise. On completionof the addition, the mixture was stirred at room temperature overnight.The mixture was diluted with water and extracted with EtOAc (×3). Thecombined organic solutions were dried (MgSO₄), and concentrated invacuo, for an extensive period of time to remove excess DMF. The residuewas applied to a silica cartridge (50 g), eluting with a gradient ofEtOAc-cyclohexane (2%-6%) to give the title compound as a colourless oil(527 mg, 14%): ¹H NMR δ (CDCl₃) 4.16 (2H, q, J=9 Hz), 3.28-3.18 (1H, m),2.66-2.55 (3H, m), 2.44 (1H, dd, J=15, 8 Hz), 1.33 (3H, d, J=7 Hz),1.31-1.23 (6H; m).

Intermediate 27 3-(Ethylthio)-1-butanol

Ethyl 3-(ethylthio)butanoate (for example, as prepared for Intermediate26) (526 mg, 2.98 mmol) was dissolved in THF (9 ml) and added dropwiseto a stirred solution of lithium aluminium hydride in ether (1.0 M, 6ml), cooled in an external ice-water bath, and under a nitrogenatmosphere. The mixture was stirred under nitrogen for 2.5 h, and thenquenched by the addition of saturated aqueous sodium sulfate solution.The mixture was filtered, and the filtrate was concentrated in vacuo togive the title compound as a colourless oil (493 mg, about 100%,contained some residual THF): ¹H NMR δ (CDCl₃) 3.89-3.72 (2H, m),3.00-2.91 (1H, m), 2.59 (2H, q, J=7.5 Hz), 1.93-1.77 (2H, m), 1.33 (3H,d, J=7 Hz), 1.27 (3H, t, J=7.5 Hz).

Intermediate 28 3-(Ethylthio)butyl methanesulfonate

3-(Ethylthio)-1-butanol (for example, as prepared for Intermediate 27)(247 mg, 1.84 mmol) was dissolved in DCM (10 ml), and the stirredsolution was cooled in an external ice-water bath. Methanesulfonylchloride (commercially available, for example, from Aldrich) (154 μl,1.99 mmol) was added and stirring was continued under a nitrogenatmosphere for 2.5 h. The reaction mixture was diluted with further DCM(5 ml) and quenched with saturated aqueous sodium hydrogen carbonate.The layers were separated and the aqueous was extracted with further DCM(×2) (hydrophobic frit). The combined organic solutions wereconcentrated in vacuo to give the title compound as a colourless oil,which later partially solidified (360 mg, 92%): ¹H NMR δ (CDCl₃)4.46-4.32 (2H, m), 3.03 (3H, s), 2.98-2.88 (1H, m), 2.57 (2H, q, J=7.5Hz), 2.03-1.87 (2H, m), 1.35 (3H, d, J=7 Hz), 1.26 (3H, t, J=7 Hz).

Intermediate 29 3-(Ethylsulfonyl)butyl methanesulfonate

3-(Ethylthio)butyl methanesulfonate (for example, as prepared forIntermediate 28) (360 mg, 1.70 mmol) was dissolved in DCM (10 ml) withstirring. The solution was treated with m-chloroperbenzoic acid(commercially available, for example, from Aldrich) (57-86%, 0.90 g, atleast 3 mmol), and the mixture was stirred at room temperature for 2.5h. Excess m-chloroperbenzoic acid was quenched by the addition ofaqueous sodium metabisulfite. Saturated aqueous sodium hydrogencarbonate and further DCM were added. The mixture was shaken, the layerswere separated, and the aqueous was extracted with further DCM. Thecombined DCM extracts were washed with further saturated aqueous sodiumhydrogen carbonate (×3), dried (MgSO₄), and were concentrated in vacuoto give the title compound as a colourless gum (393 mg, 95%): LCMSRT=1.64 min, ES+ve m/z 262 (M+NH₄)⁺

Intermediate 302-(2-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}ethyl)-1H-isoindole-1,3(2H)-dione

6-Butyl-8-(4-piperidinyloxy)quinoline (for example, as prepared forIntermediate 4) (2.44 g, 8.59 mmol) was stirred with2-(2-bromoethyl)-1H-isoindole-1,3(2H)-dione (commercially available, forexample, from Acros and/or Aldrich) (2.40 g, 9.4 mmol) and potassiumcarbonate (5.9 g, 43 mmol) in 2-butanone (75 ml) under nitrogen at 80°C. for 3 days. Further 2-(2-bromoethyl)-1H-isoindole-1,3(2H)-dione (2.4g, 9.4 mmol) was added and the heating and stirring were continued for afurther 24 h. More 2-(2-bromoethyl)-1H-isoindole-1,3(2H)-dione (1.2 g,4.7 mmol) was added and the heating and stirring were continued for afurther 24 h. The mixture was cooled and partitioned between water andDCM. The aqueous layer was extracted with more DCM (×2) and the combinedorganic layers were washed with water, dried (MgSO₄) and evaporated toan oil. This oil was re-dissolved in DCM and loaded onto a column ofsilica gel (250 g) that had been preconditioned with DCM. The column waseluted with DCM, then DCM-ethanol-0.88 s.g. aqueous ammonia solution(200:8:1) to give the title compound (2.76 g, 6.03 mmol). LCMS RT=2.91min, ES+ve m/z 458 [M+H]⁺.

Intermediate 31 1,1-Dimethylethyl(3-{44(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)carbamate

6-Butyl-8-(4-piperidinyloxy)quinoline (for example, as prepared forIntermediate 4) (437 mg, 1.54 mmol) was stirred with 1,1-dimethylethyl(3-bromopropyl)carbamate (commercially available, for example, fromAldrich) (612 mg, 2.57 mmol) and potassium carbonate (426 mg, 3.15 mmol)in 2-butanone (15 ml) under nitrogen at 80° C. overnight. The mixturewas cooled and partitioned between water and DCM. The aqueous layer wasextracted with more DCM (×2) and the combined organic layers were washedwith brine, dried (MgSO₄) and evaporated to give a yellow gum. This waspurified by flash chromatography (50 g), eluting with 0-30% methanol(containing 1% triethylamine) in DCM. The relevant fractions wereconcentrated in vacuo to give the title compound as a yellow oil (530mg, 78%). LCMS RT=2.94 min, ES+ve m/z 442 [M+H]⁺.

Intermediate 32 1,1-Dimethylethyl(4-{4-[(6-butyl-8-quinolinygoxy]-1-piperidinyl}butyl)carbamate

This was prepared in an analogous manner to that disclosed forIntermediate 31 using 6-butyl-8-(4-piperidinyloxy)quinoline (forexample, as prepared for Intermediate 4) and 1,1-dimethylethyl(4-bromobutyl)carbamate (commercially available, for example, fromAldrich) instead of 1,1-dimethylethyl (3-bromopropyl) carbamate.

Thus, for example, 6-butyl-8-(4-piperidinyloxy)quinoline (for example,as prepared for Intermediate 4) (855 mg, 3.0 mmol) was stirred with1,1-dimethylethyl (4-bromobutyl)carbamate (commercially available, forexample, from Fluka) (1.12 g, 4.5 mmol) and potassium carbonate (887 mg,6.4 mmol) in 2-butanone (30 ml) under nitrogen at 80° C. overnight. Themixture was cooled and concentrated in vacuo. The residue waspartitioned between water (25 ml) and DCM (25 ml). The aqueous layer wasextracted with more DCM (25 ml), and the combined organic layers dried(hydrophobic frit) and concentrated in vacuo. The residue was purifiedby flash chromatography (silica, 100 g), eluting with 0-15% methanol(containing 1% triethylamine) in DCM over 40 min. The relevant fractionswere concentrated in vacuo to give the title compound as a yellow gum(1.29 g, 94%). LCMS RT=3.04 min, ES+ve m/z 456 [M+H]⁺.

Intermediate 33 1,1-Dimethylethyl (5-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}pentyl) carbamate

This was prepared in an analogous manner to that disclosed forIntermediate 31 using 6-butyl-8-(4-piperidinyloxy)quinoline (forexample, as prepared for Intermediate 4), and 1,1-dimethylethyl(5-bromopentyl) carbmate (commercially available, for example, fromToronto). LCMS RT=3.04 min, ES+ve m/z 470 [M+H]⁺.

Intermediate 34 1,1-Dimethylethyl (3-{4-[(6-pentyl-8-qui nonnyl)oxy]-1-piperidinyl}propyl) carbamate

This was prepared in an analogous manner to that disclosed forIntermediate 31 using 6-pentyl-8-(4-piperidinyloxy)quinoline (forexample, as prepared for Intermediate 8) and 1,1-dimethylethyl(3-bromopropyl) carbamate (commercially available, for example, fromAldrich) with a reaction time of 7 h. LCMS RT=3.16 min, ES+ve m/z 456[M+H]⁺.

Intermediate 35(2-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}ethyl)amine

2-(2-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}ethyl)-1H-isoindole-1,3(2H)-dione(for example, as prepared for Intermediate 30) (2.76 g, 6.03 mmol) wasstirred under nitrogen in ethanol (40 ml) containing hydrazinemonohydrate (commercially available, for example, from Aldrich) (0.71ml, 15.1 mmol) at 80° C. for 2 h. The reaction was cooled with ice-waterand filtered. The filter-cake was leached with ethanol and the combinedfiltrates were evaporated to an oil containing a white solid. This solidwas mixed with DCM (about 20 ml) and filtered. The filter-cake wasleached with more DCM and the combined filtrates were evaporated to givethe title compound (2.07 g) as an oil: LCMS RT=2.32 min, ES+ve tri/z 328[M+H]⁺.

Intermediate 36(3-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)amine

1,1-Dimethylethyl(3-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)carbamate (forexample, as prepared for Intermediate 31) (493 mg, 1.12 mmol) wastreated with a solution of hydrogen chloride in dioxane (4 M, 10 ml),and stirred under nitrogen overnight at room temperature. The mixturewas concentrated in vacuo. The residue was dissolved in methanol, andapplied to a SCX-2 ion exchange cartridge (10 g) which had beenpreconditioned with methanol. The cartridge was washed with methanol(100 ml), and then eluted with 10% aqueous 0.88 s.g. ammonia in methanol(100 ml). The relevant basic fractions were concentrated in vacuo togive the title compound (292 mg, 76%). LCMS RT=1.92 min, ES+ve m/z 342(WH)'.

Intermediate 374-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)amine

This was prepared in an analogous manner to that disclosed forIntermediate 36, using 1,1-dimethylethyl(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)carbamate (forexample, as prepared for Intermediate 32).

Thus, for example, 1,1-dimethylethyl(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl) carbamate (forexample, as prepared for Intermediate 32) (1.29 g, 2.84 mmol) wasdissolved in MeOH (10 ml) and treated with a solution of hydrogenchloride in dioxane (4 M, 30 ml). The mixture was stirred under nitrogenfor 3 h at room temperature. The mixture was concentrated in vacuo. Theresidue was dissolved in methanol, and applied to a SCX-2 ion exchangecartridge (50 g, pre-conditioned with methanol). The cartridge waswashed with methanol (3 column volumes), and then eluted with 10%aqueous 0.88 s.g. ammonia in methanol (3 CV). The relevant basicfractions were concentrated in vacuo to give the title compound as ayellow gum (891 mg, 88%). LCMS RT=2.34 min, ES+ve m/z 356 [M+H]⁺.

Intermediate 38(5-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}pentyl)amine

This was prepared in an analogous manner to that disclosed forIntermediate 36, using 1,1-dimethylethyl(5-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}pentyl)carbamate (forexample, as prepared for Intermediate 33). LCMS RT=2.28 min, ES+ve m/z370 [M+H]⁺.

Intermediate 39(3-{4-[(6-Pentyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)amine

This was prepared in an analogous manner to that disclosed forIntermediate 36, using 1,1-dimethylethyl(3-{4-[(6-pentyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)carbamate (forexample, as prepared for Intermediate 34). LCMS RT=2.56 min, ES+ve m/z356 [M+H]⁺.

Intermediate 40 4-[(Ethylsulfonyl)amino]butyl ethanesulfonate

4-Amino-1-butanol (commercially available, for example, from Aldrich)(0.97 g, 11 mmol) was dissolved in DCM (50 ml) together withtriethylamine (9.0 ml, 65 mmol), and the stirred solution was cooled toapproximately 5° C. in an external ice-water bath under a nitrogenatmosphere. Ethanesutfonyl chloride (commercially available, forexample, from Aldrich) (4.09 g, 31.8 mmol), dissolved in DCM (30 ml),was added dropwise, using further DCM (20 ml) to wash in. The reactionmixture was stirred under nitrogen and allowed to warm gradually to roomtemperature over 4 h. The mixture was diluted with further DCM (100 ml)and washed with saturated aqueous sodium hydrogen carbonate (100 ml).The aqueous layer was extracted with further DCM (100 ml, ×2). Thecombined organic solutions were dried (MgSO₄) and concentrated in vacuoto give the crude product, which was used without further purificationin the reaction below (3.11 g): LCMS RT=2.06 min, ES+ve m/z 274 (M+H)⁺,291 (M+NH₄)⁺.

On another occasion, a portion of the crude material from an analogousreaction was purified by chromatography. The brown oil (792 mg) wasapplied to a silica cartridge (50 g, Flashmaster 2), eluting with 0-100%EtOAc-DCM over 40 min to give the pure title compound as a colourlessgum (621 mg): LCMS RT=2.15 min, ES+ve m/z 291 (M+NH₄)⁺.

Intermediate 41 3-Chloro-N-(1,1-dimethylethyl)-1-propanesulfonamide

To a solution of 3-chloropropanesulfonyl chloride (commerciallyavailable, for example, from Aldrich) (1 g, 6 mmol) in DCM (10 ml) in anice-water bath was added t-butylamine (commercially available, forexample, from Aldrich) (1.3 ml, 12 mmol). The solution was allowed towarm to ambient temperature and stirred for 3 h. The reaction mixturewas applied to a SCX-2 cartridge (50 g) (preconditioned with methanol)and the cartridge eluted with methanol (2 column volumes). The methanolfraction was concentrated in vacuo to give the title compound as a whitewaxy solid (1.17 g, 97%). LCMS RT=2.61 min, ES+ve m/z 214 (M+H)⁺.

Intermediate 42 N-(1,1-Dimethylethyl)ethenesulfonamide and2-chloro-N-(1,1-dimethylethyl)ethanesulfonamide (1:1)

This was prepared in an analogous manner to that disclosed forIntermediate 41, using 2-chloro-1-ethanesulfonyl chloride (commerciallyavailable, for example, from Aldrich) instead of 3-chloropropanesulfonylchloride. Yield 65%. LCMS RT=2.04 min, ES+ve m/z 164 (M+H)⁺and RT=2.22min, ES+ve m/z 215/217 (M+NH₄)⁺; ¹H NMR δ (DMSO-d₆) 6.74 (1H, dd, J=16,10 Hz), 6.0 (1H, d, J=16 Hz), 5.84 (1H, d, J=8 Hz), 3.70 (1H, t, J=8Hz), 2.86 (1H, t, J=8 Hz) and 1.20 (9H, s).

Intermediate 43 4-Chloro-N-propyl-1-butanesulfonamide

This was prepared in an analogous manner to that disclosed forIntermediate 41, using n-propylamine (commercially available, forexample, from Aldrich) instead of t-butylamine, and4-chloro-1-butanesulfonyl chloride (prepared according to White, E. H.;Lim, H. M. J. Org. Chem. 52, 1987, 11, 2162-2166) instead of3-chloropropane sulfonyl chloride. Yield 88%. LCMS RT=2.54 min, ES+vem/z 214 (M+H)⁺.

EXAMPLES Example 16-Butyl-8-({112-(ethylsulfonyl)ethyl]-4-piperidinyl}oxy)quinoline,dihydrochloride salt

A mixture of 6-butyl-8-(4-piperidinyloxy)quinoline (for example, asprepared for Intermediate 4) (35 mg, 0.12 mmol) sodium bicarbonate (50mg, 0.6 mmol) in DMF (1 ml) was treated with ethyl vinyl sulfone(commercially available, for example, from Aldrich) (0.6 ml, 5.7 mmol)and the suspension was heated to 100° C. for 15 min in a Smith Creator™microwave oven. The mixture was diluted with methanol and applied to anSCX-2 cartridge (10 g) eluting with methanol, followed by 10% aqueous0.88 s.g. ammonia in methanol. The ammoniacal fractions were evaporatedunder reduced pressure; the residue was dissolved in methanol andre-evaporated. The residue (43 mg) was purified by MDAP and theappropriate fractions were combined and evaporated under reducedpressure to give the formate salt of the title compound (34 mg). Theformate salt was then dissolved in methanol (10 ml) and treated with1.25 M hydrogen chloride in methanol (0.2 ml, 0.25 mmol) and the solventremoved in vacuo to give the title compound (37 mg): LCMS RT=2.71 min,ES+ve m/z 405 (M+H)⁺.

Example 2 6-Butyl-8-[(1-{2-[(1,1-dimethylethyl)sulfonyl]ethyl}-4-piperidinyl)oxy]quinoline, dihydrochloridesalt

A mixture of 6-butyl-8-(4-piperidinyloxy)quinoline (for example, asprepared for Intermediate 4) (80 mg, 0.28 mmol), sodium iodide (37 mg,0.25 mmol), sodium bicarbonate (168 mg, 2.0 mmol) and 2-chloroethyl1,1-dimethylethyl sulfone (for example, as prepared for Intermediate 12)(208 mg, 1.1 mmol) in DMF (2 ml) was heated at 150° C. for 15 min in aSmith Creator™ microwave oven. The reaction mixture was applied to anSCX-2 cartridge (20 g) preconditioned with methanol and was eluted withmethanol, followed by 10% aqueous 0.88 s.g. ammonia in methanol. Theammoniacal fractions were combined and concentrated in vacuo and theresidue (118 mg) was purified by MDAP (×2). Appropriate fractions werecombined and concentrated in vacuo to give the free base of the titlecompound (10 mg, 8%): This was diluted with methanol and treated with1.25 M hydrogen chloride solution in methanol (0.05 ml) and the solutionwas evaporated in vacuo to give the title compound (12 mg): LCMS RT=2.73min, ES+ve m/z 433 (M+H)⁺.

Example 3 6-Butyl-8-({1-[3-(methylsulfonyl)propyl]-4-piperidinyl}oxy)quinoline,dihydrochloride salt

A mixture of 6-butyl-8-(4-piperidinyloxy)quinoline (for example, asprepared for Intermediate 4) (80 mg, 0.28 mmol), sodium iodide (30 mg,0.2 mmol) and sodium bicarbonate (110 mg, 1.3 mmol) in DMF (2 ml) wastreated with a solution of mixture of 3-bromopropyl methyl sulfone and3-chloropropyl methyl sulfone (for example, as prepared for Intermediate19) (124 mg) in DMF (0.5 ml) and the mixture was heated at 150° C. for15 min in a Smith Creator™ microwave oven. The reaction mixture wasapplied to an SCX-2 cartridge (10 g), preconditioned with methanol, andeluted with methanol, followed by 10% aqueous 0.88 s.g. ammonia inmethanol. The ammoniacal fractions were combined and concentrated invacuo and the residue (126 mg) was purified by MDAP. Appropriatefractions were combined and concentrated in vacuo and the residue (30mg) was applied to an SCX-2 cartridge (5 g), pre-conditioned withmethanol and eluted with methanol, followed by 10% aqueous 0.88 s.g.ammonia in methanol. The ammoniacal fractions were combined andconcentrated in vacuo to give the free base of the title compound (21mg, 18%): This was treated with 1.25 M hydrogen chloride solution inmethanol (0.15 ml) and the solution was evaporated in vacuo to give thetitle compound (22 mg, 89%): LCMS RT=2.49 min, ES+ve m/z 405 (M+H)⁺.

Example 4 6-Butyl-8-({1-[3-(ethylsulfonyl)propyl]-4-pi peri dinyl}oxy)qui noli ne

Preparation A (Free Base):

A mixture of 6-butyl-8-(4-piperidinyloxy)quinoline (for example, asprepared for Intermediate 4) (392 mg, 1.38 mmol), sodium iodide (70 mg,0.46 mmol) and sodium bicarbonate (580 mg, 7 mmol) was treated with asolution of 3-(ethylsulfonyl)propyl 4-methylbenzenesulfonate (forexample, as prepared for Intermediate 16) (422 mg, 1.38 mmol) in DMF (10ml), and the mixture was heated to 100° C. under nitrogen for 5.75 h,then for 3 days at room temperature. More 3-(ethylsulfonyl)propyl4-methylbenzenesulfonate (60 mg, 0.2 mmol) was added, and the mixturewas stirred at room temperature for 20 h and then heated at 100° C. for4 h. LCMS indicated no significant change beyond the initial 3 hreaction time and the mixture was partitioned between EtOAc and aqueoussodium bicarbonate. The organic solution was washed with aqueous sodiumbicarbonate (×3), brine (×2), dried (MgSO₄), and evaporated in vacuo.The residue (722 mg) was dissolved in DCM and purified by chromatographyon Flashmaster 2 (silica, 70 g cartridge) eluting with 0-15% methanol(containing 1% triethylamine) —DCM over 40 min. Appropriate fractionswere combined and evaporated in vacuo to give the title compound (352mg, 61%): LCMS RT=2.42 min, ES+ve m/z 419 (M+H)⁺; ¹H NMR δ (CDCl₃) 8.88(1H, dd, J=4, 2 Hz), 8.04 (1H, dd, J=8, 2 Hz), 7.37 (1H, dd, J=8, 4 Hz),7.18 (1H, br s), 6.96 (1H, d, J=1 Hz), 4.64-4.56 (1H, m), 3.13-2.99 (4H,m), 2.97-2.88 (2H, m), 2.76 (2H, t, J=8 Hz), 2.55 (2H, t, J=7 Hz),2.36-2.25 (2H, m), 2.22-2.13 (2H, m), 2.10-1.99 (4H, m), 1.74-1.58 (4H,m), 1.43 (3H, t, J=7 Hz), 0.96 (3H, t, J=7 Hz).

Preparation B (Dihydrochloride Salt):

To a solution of 6-butyl-8-(4-piperidinyloxy)quinoline (for example, asprepared for Intermediate 4) (0.26 g, 0.91 mmol) in DMF (5 ml) was addeda mixture of 3-chloropropyl ethyl sulfone (for example, as prepared forIntermediate 14) (0.182 g, 1.07 mmol), sodium iodide (0.157 g, 1.05mmol), and then potassium carbonate (0.152 g, 1.1 mmol). The suspensionwas heated to 150° C. for 15 min in a Smith Creator™ microwave oven,with fixed hold time on. The mixture was applied to an SCX-2 cartridge(20 g), preconditioned with methanol, and the cartridge washed withmethanol (2 column volumes). The cartridge was eluted with 10% 0.88 s.g.ammonia in methanol (2 column volumes), the basic fraction wasconcentrated in vacuo and the residue (0.4 g) was purified byFlashmaster II chromatography (silica, 70 g cartridge), eluting with0-25% methanol in DCM over 40 min. The appropriate fractions werecombined and evaporated in vacuo to give the free base of the titlecompound (295 mg). LCMS RT=2.7 min, ES+ve m/z 419 (M+H)⁺; ¹H NMR δ(CD₃OD): 8.45 (1H, t, J=4, 2 Hz), 8.03 (1H, dd, J=8, 2 Hz), 7.30 (1H,dd, J=8, 4 Hz), 7.08 (1 H, br s), 6.92 (1 H, br s), 4.51 (1 H, m),3.0-2.9 (4H, m), 2.80 (2H, m), 2.60 (2H, t, J=8 Hz), 2.42 (2H, t, J=8Hz), 2.25 (2H, m), 1.93-2.0 (2H, m), 1.9-1.77 (4H, m), 1.57-1.47 (2H,m), 1.28-1.2 (2H, m), 1.18 (3H, t, J=8 Hz) and 0.78 (3H, t, J=8 Hz). Toa solution of the free base of the title compound (295 mg, 0.7 mmol) inmethanol (2 ml) was added 1.25 M hydrogen chloride in methanol (1.7 ml).The solvent was removed using a stream of nitrogen and then dried invacuo to give the title compound as a solid (287 mg, 64%). LCMS RT=2.69min, ES+ve m/z 419 (M+H)⁺. Anal. Found: C, 55.30; H, 7.45; N, 5.41%Calcd for (C₂₃H₃₄N₂O₃S. 2HCl.0.5H₂O): C, 55.19; H, 7.45; N, 5.60%.

Example 5 6-Butyl-8-({1-{3-(propylsulfonyl)propyl]-4-piperidinyl}oxy)quinoline,dihydrochloride salt

A mixture of 6-butyl-8-(4-piperidinyloxy)quinoline (for example, asprepared for Intermediate 4) (284 mg, 1.00 mmol), sodium iodide (150 mg,1.0 mmol) and sodium bicarbonate (700 mg, 8 mmol) was treated with asolution of a mixture of 3-bromopropyl propyl sulfone and 3-chloropropylpropyl sulfone (for example, as prepared for Intermediate 18) (4:3, 494mg) in DMF (6 ml) and the mixture was heated at 100° C. for 18 h undernitrogen. The reaction mixture was allowed to cool to room temperatureand partitioned between EtOAc and water. The organic phase was washedwith water (×4), brine, dried (MgSO₄), and evaporated in vacuo. Theresidue (681 mg) was dissolved in methanol and applied to an SCX-2cartridge (50 g) eluting with methanol, followed by 10% aqueous 0.88s.g. ammonia in methanol. The ammoniacal fractions were combined andevaporated in vacuo. The residue (0.51 g) was dissolved in DCM andpurified by chromatography on Flashmaster 2 (silica, 70 g cartridge)eluting with 0-15% methanol (containing 1% triethylamine) in DCM over 40min. The appropriate fractions were combined and evaporated and theresidue (183 mg) was further purified by MDAP to give the formate saltof the title compound (132 mg, 27%): LCMS RT=2.70 min, ES+ve m/z 433(M+H)⁺. The formate salt (132 mg, 0.3 mmol) was dissolved in methanol (3ml) and treated with 1.25 M hydrogen chloride in methanol (0.5 ml). Thesolvent was removed in vacuo to give the title compound (127 mg, 84%)LCMS RT=2.71 min, ES+ve m/z 433 (M+H)⁺.

Example 66-Butyl-8-[(1-{3-[(1-methylethyl)sulfonyl]propyl}-4-piperidinyl)oxy]quinoline,dihydrochloride salt

A mixture of 6-butyl-8-(4-piperidinyloxy)quinoline (for example, asprepared for Intermediate 4) (83 mg, 0.29 mmol), sodium iodide (47 mg,0.3 mmol) and sodium bicarbonate (168 mg, 2 mmol) was treated with amixture of 3-bromopropyl 1-methylethyl sulfone and 3-chloropropyl1-methylethyl sulfone (for example, as prepared for Intermediate 20)(57:43, 90 mg) in DMF (1.5 ml) and the mixture was heated at 150° C. for15 min in a Smith Creator™ microwave oven. The reaction mixture wasapplied to an SCX-2 cartridge (20 g), preconditioned with methanol, andeluted with methanol, followed by 10% aqueous 0.88 s.g. ammonia inmethanol. The ammoniacal fractions were combined and concentrated invacuo. The residue (160 mg) was purified by MDAP to give the formatesalt of the title compound (102 mg, 73%). The formate salt (100 mg, 0.2mmol) was treated with 1.25 M hydrogen chloride in methanol (4 ml) andthe solvent was removed in vacuo to give the title compound (103 mg,99%): LCMS RT=2.53 min, ES+ve m/z 433 (M+H)⁺.

Example 7 6-Butyl-8-[(1-{3-[(1,1-dimethylethyl)sulfonyl]propyl}-4-piperidinyl)oxy]quinoline, formate salt

A mixture of 6-butyl-8-(4-piperidinyloxy)quinoline (for example, asprepared for Intermediate 4) (28 mg, 0.10 mmol), sodium iodide (34 mg,0.23 mmol) and sodium bicarbonate (60 mg, 0.7 mmol) was treated with amixture of 3-bromopropyl 1,1-dimethylethyl sulfone and 3-chloropropyl1,1-dimethylethyl sulfone (for example, as prepared for Intermediate 17)(1:1, 40 mg) in DMF (1.5 ml) and heated to at 150° C. for 15 min in aSmith Creator™ microwave oven. The reaction mixture was applied to anSCX-2 cartridge (10 g), preconditioned with methanol, and eluted withmethanol, followed by 10% aqueous 0.88 s.g. ammonia in methanol. Theammoniacal fractions were combined and concentrated in vacuo and theresidue was purified by MDAP to give the title compound (20 mg, 40%):LCMS RT=2.76 min, ES+ve m/z 447 (M+H)⁺; ¹H NMR δ (CD₃OD) 8.78 (1H, dd,J=4, 2 Hz), 8.44 (1.6H, s), 8.24 (1H, dd, J=8, 2 Hz), 7.52 (1H, dd, J=8,4 Hz), 7.32 (1H, br s), 7.19 (1H, br s), 5.03-4.96 (1 H, m), 3.68-3.59(2H, m), 3.40-3.26 (4H, obscured by CD₃OD), 3.22 (2H, t, J=7 Hz), 2.79(2H, t, J=7 Hz), 2.35-2.21 (6H, m), 1.75-1.67 (2H, m), 1.45-1.35 (2H,m), 1.40 (9H, s), 0.96 (3H, t, J=7 Hz).

Example 86-Butyl-8-({1-[3-(cyclopentylsulfonyl)propyl]-4-piperidinyl}oxy)quinoline,formate salt (1:1)

A suspension of 3-(cyclopentylsulfonyl)propyl methanesulfonate (forexample, as prepared for Intermediate 25) (0.081 g, 0.3 mmol),6-butyl-8-(4-piperidinyloxy)quinoline (for example, as prepared forIntermediate 4) (0.102 g, 0.360 mmol), sodium iodide (40 mg, 0.3 mmol)and sodium hydrogen carbonate (200 mg, 2.39 mmol) in dry DMF (2 ml) washeated in a Smith Creator™ microwave oven at 150° C. for 15 min. Thereaction mixture was applied to an SCX-2 cartridge (20 g),preconditioned with methanol. The cartridge was washed with methanol(4×25 ml) and then eluted with 10% aqueous 0.88 s.g. ammonia in methanol(4×25 ml). The solvents were removed in vacuo and the resultant residuepurified by MDAP to afford the title compound (53 mg): LCMS RT=2.81 min;ES+ve m/z 459 (M+H)⁺

Example 9 6-Butyl-8-[(1-{4-[(1,1-dimethylethyl)sulfonyl]butyl}-4-piperidinyl)oxy]quinoline, formate salt

A mixture of 6-butyl-8-(4-piperidinyloxy)quinoline (for example, asprepared for Intermediate 4) (65 mg, 0.23 mmol), sodium iodide (47 mg,0.3 mmol), sodium bicarbonate (190 mg, 2.2 mmol) and 4-bromobutyl1,1-dimethylethyl sulfone (for example, as prepared for Intermediate 22)(94 mg) in DMF (2 ml) was heated in a Smith Creator™ microwave oven at150° C. for 20 min. The reaction mixture was applied to an SCX-2cartridge (10 g), preconditioned with methanol, and eluted withmethanol, followed by 10% aqueous 0.88 s.g. ammonia in methanol. Theammoniacal fractions were combined and concentrated in vacuo and theresidue (100 mg) was purified by MDAP to give the title compound (58 mg,46%): LCMS RT=2.65 min, ES+ve m/z 461 (M+H)⁺.

Example 106-Butyl-8-({1-[3-(ethylsulfonyl)butyl]-4-piperidinyl}oxy)quinoline,dihydrochloride salt

A mixture of 6-butyl-8-(4-piperidinyloxy)quinoline (for example, asprepared for Intermediate 4) (88 mg, 0.31 mmol), sodium hydrogencarbonate (183 mg, 2.18 mmol) and sodium iodide (92 mg, 0.61 mmol) inDMF (3 ml) was treated with 3-(ethylsulfonyl)butyl methanesulfonate (forexample, as prepared for Intermediate 29) (143 mg, 0.59 mmol) and thesuspension was heated to 150° C. for 30 min in a Smith Creator™microwave oven. The mixture was diluted with methanol and applied to anSCX-2 cartridge (50 g) eluting with methanol, followed by 10% aqueous0.88 s.g. ammonia in methanol. The relevant fractions were concentrated,and the residue was purified by MDAP. The appropriate fractions werecombined and concentrated in vacuo to give the title compound as themonoformate salt (68 mg, 46%): LCMS RT=2.72 min, ES+ve m/z 433 (M+H)⁺; Aportion of this material (12 mg) was dissolved in methanol and treatedwith 1.25 M hydrogen chloride in methanol (0.5 ml, excess). Thevolatiles were removed under a stream of nitrogen to give the titlecompound (13 mg) as a pale yellow glass: LCMS RT=2.68 min, ES+ve m/z 433(M+H)⁺.

Example 118-({1-[3-(Ethylsulfonyl)propyl]-4-piperidinyl}oxy)-6-pentylquinoline,dihydrochloride salt

A mixture of 6-pentyl-8-(4-piperidinyloxy)quinoline (for example, asprepared for Intermediate 8) (72 mg, 0.24 mmol), sodium hydrogencarbonate (144 mg, 1.7 mmol), sodium iodide (30 mg, 0.2 mmol) and3-(ethylsulfonyl)propyl 4-methylbenzenesulfonate (for example, asprepared for Intermediate 16) (68 mg, 0.2 mmol) in DMF (2 ml) was heatedto 150° C. for 15 min in a Smith Creator™ microwave oven. The mixturewas applied to an SCX-2 cartridge (20 g) eluting with methanol, followedby 10% aqueous 0.88 s.g. ammonia in methanol. The relevant fractionswere concentrated, and the residue was applied to a silica cartridge (50g), eluting with DCM-ethanol-aqueous 0.88 s.g. ammonia (200:8:1 then100:8:1). One fraction contained clean product, but the materialobtained from concentration of a second fraction required furtherpurification by MDAP. The relevant fractions from the MDAP purificationwere concentrated in vacuo and combined with the pure material from theearlier purification. This material (12 mg) was dissolved in methanoland treated with 1.25 M hydrogen chloride in methanol (0.5 ml, excess).The volatiles were removed under a stream of nitrogen to give the titlecompound (36 mg, 30%): LCMS RT=2.89 min, ES+ve m/z 433 (M+H)⁺.

Example 126-Butyl-8-[((3R)-1-{3-[(1,1-dimethylethyl)sulfonyl]propyl}-3-pyrrolidinyl)oxy]quinoline, dihydrochloride salt

To a solution of 6-butyl-8-[(3R)-3-pyrrolidinyloxy]quinoline (forexample, as prepared for Intermediate 10) (0.130 g, 0.481 mmol), in DMF(3 ml) was added a mixture of 3-bromopropyl 1,1-dimethylethyl sulfoneand 3-chloropropyl 1,1-dimethylethyl sulfone (for example, as preparedfor Intermediate 17) (1:1, 0.215 g, 0.96 mmol), sodium iodide (0.144 g,0.96 mmol), then potassium carbonate (0.133 g, 0.96 mmol). Thesuspension was heated to 150° C. for 15 min in a Smith Creator™microwave oven with fixed hold time on. The mixture was applied to anSCX-2 cartridge (20 g), preconditioned with methanol, and the cartridgewashed with methanol (2 column volumes). The cartridge was eluted with10% 0.88 s.g. ammonia in methanol (2 column volumes) and the basicfraction concentrated in vacuo. The residue (0.2 g) was purified by MDAPand the appropriate fractions combined and concentrated in vacuo. Theresidue (0.113 g) was further purified by Flashmaster II chromatography(50 g cartridge) eluting with 0-25% methanol in DCM over 40 min. Theappropriate fractions were combined and the solvent removed in vacuo (70mg, 33%). To a portion of this material (29 mg, 0.067 mmol) in methanol(0.5 ml) was added 1.25 M hydrogen chloride in methanol (0.3 ml). Thesolvent was removed using a stream of nitrogen to leave the titlecompound as white solid (34 mg). LCMS RT=2.97 min, ES+ve m/z 433 (M+H)⁺.

Example 136-Butyl-8-{(1-(1,1-dioxidotetrahydro-3-thienyl)-4-piperidinyl]oxy}quinoline

To a solution of 6-butyl-8-(4-piperidinyloxy)quinoline (for example, asprepared for Intermediate 4) (0.15 g, 0.53 mmol) in THF (5 ml) was added2,3-dihydrothiophene 1,1-dioxide (commercially available, for example,from AKOS) (0.150 g, 1.27 mmol). The solution was heated to 80° C. for2.5 h. To the solution at ambient temperature was added a further amountof 2,3-dihydrothiophene 1,1-dioxide (0.150 g, 1.27 mmol) and thesolution stirred overnight at ambient temperature. The solution washeated to reflux for 2 h and then at ambient temperature for 7 days. Thereaction was applied to an SCX-2 cartridge (20 g), preconditioned withmethanol, and the cartridge washed with methanol (2 column volumes). Thecartridge was eluted with 10% 0.880 s.g. ammonia in methanol (2 columnvolumes) and the basic fractions concentrated in vacuo. The residue waspurified by MDAP and the appropriate fractions combined and evaporated.The combined fractions were applied to an SCX-2 cartridge (20 g),preconditioned with methanol, and the cartridge washed with methanol.The cartridge was eluted with 10% 0.88 s.g. ammonia in methanol (2column volumes) and the basic fractions concentrated in vacuo to givethe title compound (17 mg, 8%). LCMS RT=2.59 min, ES+ve m/z 403 (M+H)⁺.

Example 14N-(2-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}ethyl]ethanesulfonamide,dihydrochloride salt

This was prepared in an analogous manner to that disclosed for Example24 using (2-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}ethyl)amine(for example, as prepared for Intermediate 35) (26 mg, 0.08 mmol),triethylamine (56 μl, 0.4 mmol), and ethanesulfonyl chloride(commercially available, for example, from Aldrich) (19 μl, 0.2 mmol) inDCM (2 ml). The title compound was obtained as the formate salt: LCMSRT=2.36 min, ES+ve m/z 420 (M+H)⁺. The material was dissolved inmethanol and treated with 1.25 M hydrogen chloride in methanol (0.6 ml,excess). The volatiles were removed under a stream of nitrogen to givethe title compound (15 mg, 38%); LCMS RT=2.68 min, ES+ve m/z 420 (M+H)⁺.

Example 15N-(2-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}ethyl)-2-methyl-1-propanesulfonamide,dihydrochloride salt

This was prepared in an analogous manner to that disclosed for Example24 using (2-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}ethyl)amine(for example, as prepared for Intermediate 35) (20 mg, 0.06 mmol),triethylamine (56 μl, 0.4 mmol), and isobutane sulfonyl chloride(commercially available, for example, from Aldrich) (26 μl, 0.2 mmol) inDCM (2 ml). The title compound was obtained as the formate salt: LCMSRT=2.97 min, ES+ve m/z 448 (M+H)⁺. The material was dissolved inmethanol and treated with 1.25 M hydrogen chloride in methanol (0.6 ml,excess). The volatiles were removed under a stream of nitrogen to givethe title compound (6 mg, 19%); LCMS RT=2.94 min, ES+ve m/z 448 (M+H)⁺.

Example 16N-(2-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}ethyl)benzenesulfonamide,dihydrochloride salt

(2-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}ethyl)amine (forexample, as prepared for Intermediate 35) (50 mg, 0.15 mmol) was stirredwith triethylamine (0.1 ml, 0.7 mmol) in DCM (2 ml) at room temperatureunder nitrogen and benzenesulphonyl chloride (commercially available,for example, from Aldrich) (29 μL, 0.22 mmol) was added. After 20 min,LCMS showed the reaction was complete. The solution was poured onto aBond Elute silica cartridge (10 g), preconditioned with DCM. Thecartridge was eluted with this solvent, and then DCM-ethanol-0.88 s.g.aqueous ammonia solution (200:8:1) to give, after evaporation, the crudefree base of the title compound (55 mg). This was dissolved indimethylsulfoxide-methanol (1:1; 1 ml) and purified by MDAP to give,after evaporation, the formate salt of the title compound: LCMS RT=2.96min, ES+ve m/z 468 (M+H)⁺. 1.25 M hydrogen chloride in methanol (0.75ml, excess) was added to this material and the solution was evaporatedto dryness and dried to give the title compound (39 mg, 48%): LCMSRT=2.95 min, ES+ve m/z 468 (M+H)⁺.

Example 17N-(3-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)ethanesulfonamide,dihydrochloride salt

(3-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)amine (forexample, as prepared for Intermediate 36) (30 mg, 0.09 mmol) wasdissolved in DCM (1 ml), and treated with triethylamine (38 μl, 0.27mmol), and ethanesulfonyl chloride (commercially available, for example,from Aldrich) (17 μl, 0.18 mmol). The mixture was stirred in a stopperedvial at room temperature for 1 h, then left to stand at room temperatureovernight. The mixture was diluted with methanol and applied to an SCX-2cartridge (5 g) eluting with methanol, followed by 10% aqueous 0.88 s.g.ammonia in methanol. The relevant fractions were concentrated, and theresidue was purified by MDAP. The appropriate fractions were combinedand concentrated to give the title compound as the monoformate salt (29mg, 67%): LCMS RT=2.62 min, ES+ve m/z 434 (M+H)⁺. The material wasdissolved in methanol and treated with 1.25 M hydrogen chloride inmethanol (excess). The volatiles were removed under a stream of nitrogento give the title compound (30 mg): LCMS RT=2.63 min, ES+ve m/z 434(M+H)⁺.

Example 18N-(3-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)-1-propanesulfonamide,dihydrochloride salt

This was prepared in an analogous manner to that disclosed for Example24 using (3-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)amine(for example, as prepared for Intermediate 36) (30 mg, 0.09 mmol),triethylamine (38 μl, 0.27 mmol), and propanesulfonyl chloride(commercially available, for example, from Aldrich) (20 μl, 0.18 mmol)in DCM (1 ml). The title compound was obtained as the partial formatesalt (approximately 0.5 equivalents formate) (36 mg, 85%). The materialwas dissolved in methanol and treated with 1.25 M hydrogen chloride inmethanol (excess). The volatiles were removed under a stream of nitrogento give the title compound (30 mg): LCMS RT=2.73 min, ES+ve m/z 448(M+H)⁺.

Example 19N-(3-{(4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)-2-propanesulfonamide,dihydrochloride salt

(3-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)amine (forexample, as prepared for Intermediate 36) (30 mg, 0.09 mmol) wasdissolved in DCM (1 ml), and treated with triethylamine (38 μl, 0.27mmol), and 2-propanesulfonyl chloride (commercially available, forexample, from Aldrich) (20 μl, 0.18 mmol). The mixture was stirred in astoppered vial at room temperature for 1 h, then left to stand at roomtemperature overnight. LCMS analysis indicated that reaction was notcomplete. Further triethylamine (38 μl, 0.27 mmol), and2-propanesulfonyl chloride (17 μl, 0.18 mmol) were added and the mixturestirred at room temperature for 1.5 h. LCMS analysis indicated thatreaction was still not complete. Further triethylamine (19 μl, 0.14mmol), and 2-propanesulfonyl chloride (10 μl, 0.09 mmol) were added andthe mixture stirred at room temperature overnight. The mixture wasdiluted with methanol and applied to an SCX-2 cartridge (5 g) elutingwith methanol, followed by 10% aqueous 0.88 s.g. ammonia in methanol.The relevant fractions were concentrated, and the residue was purifiedby MDAP. The appropriate fractions were combined and concentrated, butthe product was found to contain an impurity, thought to be(3-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)sulfamic acid.The material was dissolved in methanol and applied to an aminopropylcartridge (5 g) eluting with methanol. The relevant fractions werecombined and concentrated to give the title compound as the free base:LCMS RT=2.68 min, ES+ve ink 448 (M+H)⁺. The material was dissolved inmethanol and treated with 1.25 M hydrogen chloride in methanol (0.5 ml,excess). The volatiles were removed under a stream of nitrogen to givethe title compound (13 mg, 27%): LCMS RT=2.80 min, ES+ve m/z 448 (M+H)⁺.

Example 20N-(3-{4-[(6-Pentyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)ethanesulfonamide,dihydrochloride salt

This was prepared in an analogous manner to that disclosed for Example24 using (3-{4-[(6-pentyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)amine(for example, as prepared for Intermediate 39) (37 mg, 0.1 mmol),triethylamine (18 μl, 0.13 mmol), and ethanesulfonyl chloride(commercially available, for example, from Aldrich) (12 μl, 0.12 mmol)in DCM (2 ml). The title compound was obtained as the formate salt: LCMSRT=2.90 min, ES+ve m/z 448 (M+H)⁺. The material was dissolved inmethanol and treated with 1.25 M hydrogen chloride in methanol (0.5 ml,excess). The volatiles were removed under a stream of nitrogen to givethe title compound as a yellow gum (24 mg, 46%): LCMS RT=2.86 min, ES+vem/z 448 (M+H)⁺.

Example 21N-(3-{4-[(6-Pentyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)-1-propanesulfonamide,dihydrochloride salt

This was prepared in an analogous manner to that disclosed for Example24 using (3-{4-[(6-pentyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)amine(for example, as prepared for Intermediate 39) (35 mg, 0.1 mmol),triethylamine (18 μl, 0.13 mmol), and 1-propanesulfonyl chloride(commercially available, for example, from Aldrich) (14 μl, 0.12 mmol)in DCM (2 ml). The title compound was obtained as the formate salt: LCMSRT=2.98 min, ES+ve m/z 462 (M+H)⁺. The material was dissolved inmethanol and treated with 1.25 M hydrogen chloride in methanol (0.5 ml,excess). The volatiles were removed under a stream of nitrogen to givethe title compound as a yellow gum (24 mg, 45%): LCMS RT=2.98 min, ES+vem/z 462 (M+H)⁺.

Example 22N-(4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)methanesulfonamide,dihydrochloride salt

This was prepared in an analogous manner to that disclosed for Example24 using (4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)amine(for example, as prepared for Intermediate 37) (40 mg, 0.11 mmol),triethylamine (24 μl, 0.18 mmol), and methanesulfonyl chloride(commercially available, for example, from Aldrich) (10 μl, 0.14 mmol)in DCM (2 ml). The title compound was obtained as the formate salt: LCMSRT=2.65 min, ES+ve m/z 434 (M+H)⁺. The material was dissolved inmethanol and treated with 1.25 M hydrogen chloride in methanol (0.5 ml,excess). The volatiles were removed under a stream of nitrogen to givethe title compound (20 mg, 36%); LCMS RT=2.65 min, ES+ve m/z 434 (M+H)⁺.

Example 23AN-(4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide

Preparation A:

6-Butyl-8-(4-piperidinyloxy)quinoline (for example, as prepared forIntermediate 4) (575 mg, 2.02 mmol) and 4-[(ethylsulfonyl)amino]butylethanesulfonate (for example, as prepared for Intermediate 40) (1.10 g,impure, estimated as 2.8 mmol) were dissolved in DMF (20 ml). Sodiumhydrogen carbonate (845 mg, 10.1 mmol) and sodium iodide (602 mg, 4.02mmol) were added. The mixture was heated at 60° C. with stirringovernight (16 h) under a nitrogen atmosphere. LCMS analysis showed thatunreacted starting material was present, so further4-[(ethylsulfonyl)amino]butyl ethanesulfonate (402 mg, impure, estimatedas 1.0 mmol) and DMF (5 ml) were added and the mixture was heated for afurther 10 h. The mixture was diluted with water (100 mL) and extractedwith toluene (100 ml, then 50 ml×3). The combined organic extracts weredried (MgSO₄) and concentrated in vacuo to give the crude material as abrown oil (1.89 g). This was applied to an SCX-2 cartridge (50 g,pre-conditioned with methanol [100 mL] then with acetonitrile [100 mL]),eluting with acetonitrile (200 ml) (or, alternatively methanol),followed by 10% aqueous 0.88 s.g. ammonia in acetonitrile (300 ml) (or,alternatively methanol). The basic fractions were concentrated in vacuoto give a brown gum (approximately 600 mg). This was applied to a silicacartridge (50 g), eluting with DCM-ethanol-aqueous 0.88 s.g. ammonia(200:8:1, 418 ml, then 150:8:1, 477 ml, then 100:8:1, 436 ml). Relevantfractions were concentrated in vacuo to give the title compound (freebase) as a brown oil (522 mg, 58%): LCMS RT=2.60 min, ES+ve m/z 448(M+H)⁺; ¹H NMR δ (CD₃OD) 8.72 (1 H, dd, J=4, 2 Hz), 8.20 (1 H, dd, J=8,2 Hz), 7.47 (1 H, dd, J=8, 4 Hz), 7.25 (1H, s), 7.09 (1H, d, J=1.5 Hz),4.72-4.64 (1H, m), 3.09-2.99 (4H, m), 2.98-2.90 (2H, m), 2.78 (2H, t,J=7.5 Hz), 2.47-2.36 (4H, m), 2.18-2.09 (2H, m), 2.05-1.94.

Preparation B:

(4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)amine (forexample, as prepared for Intermediate 37) (248 mg, 0.7 mmol) wasdissolved in DCM (5 ml), and treated with triethylamine (156 μl, 1.12mmol), and ethanesulfonyl chloride (commercially available, for example,from Aldrich) (80 μl, 0.84 mmol). The mixture was stirred at roomtemperature for 2 h, then left to stand at room temperature overnight.The mixture was washed with saturated aqueous sodium hydrogen carbonate,passed through a hydrophobic frit and the organic solution wasconcentrated in vacuo. The residue was applied to a silica cartridge (20g), eluting with DCM-ethanol-aqueous 0.88 s.g. ammonia (100:8:1). Therelevant fractions were concentrated in vacuo to give the title compound(as the free base) as a yellow gum (167 mg). LCMS RT=2.66 min, ES+ve m/z448 (M+H)⁺; ¹H NMR δ (CD₃OD) 8.72 (1H, dd, J=4, 1.5 Hz), 8.21 (1H, dd,J=8, 1.5 Hz), 7.48 (1H, dd, J=8, 4 Hz), 7.26 (1H, s), 7.10 (1H, s),4.74-4.64 (1H, m), 3.10-2.92 (6H, m), 2.78 (2H, t, J=7.5 Hz), 2.50-2.38(4H, m), 2.20-2.10 (2H, m), 2.08-1.95 (2H, m), 1.76-1.53 (6H, m),1.47-1.36 (2H, m), 1.30 (3H, t, J=7 Hz), 0.97 (3H, t, J=7 Hz).

Example 23BN-(4{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide,dihydrochloride salt

For this method the following abbreviations are used:

-   eqv: equivalent (1 eq=1 mole reagent per 1 mole of starting    material)-   kg: kilograms-   L: litres-   vol: volume (1 vol=1 ml per gram starting material)-   wt: weight (1 wt=1 g reagent per 1 g starting material)

Intermediate 2 (Stage 1)

-   6-Butyl-8-fluoroaulnoline

Under nitrogen, 6-chloro-8-fluoroquinoline (for example, as prepared forIntermediate 5) (4.6 kg, 1.0 eqv) was added to N-methylpyrrolidinone (46L, 10 vol). To this mixture, ferric acetylacetonate (0.89 kg, 0.1 eqv)was added and the reaction mass cooled to 0 to −10° C. A solution ofn-butyl magnesium chloride (commercially available, for example, fromAldrich) (14.84 L, 1.35 eqv of 2.3M grignard in tetrahydrofuran) wasadded slowly over approximately 4 hours at between 0 to −10° C. and thereaction was stirred for 10 to 20 min. The progress of the reaction wasmonitored by HPLC. As there was more than 2% starting material a furtherportion of n-butyl magnesium chloride was added (0.52 L, 0.05 eqv of2.3M grignard in tetrahydrofuran) at 0 to −10° C. over 10 to 30 min.After passing the HPLC (starting material not more than 2%), thereaction mixture was quenched with ammonium chloride solution (4.6 kg, 1wt, in 101 L water) keeping the temperature below 35° C., an thereaction mixture was stirred at approximately 27° C. for 15-30 min. Adilute solution of aqueous HCl (3.5 vol, 14.6 L [made up as bulksolution of 4.6 L 35% HCl in 13.8 L water]) was then added into thereaction mixture until pH 1-2 was reached. The reaction mass wasextracted at pH 1 to 2 with ethyl acetate (46 L, then 28 L×3). Thecombined organic layers were then washed with water (69 L, 15 vol) anddilute ammonia solution (46 L [41.4 L water and 4.6 L 22.38% aqueousammonia solution). The organic layer was washed with water (55.2 L×3),the organic layer was separated and concentrated in vacuo (vacuum noless than 600 mm Hg), keeping the temperature below 70° C. Toluene (4.6L, 1 vol) was then added and the mixture concentrated in vacuo (vacuumno less than 600 mm Hg), keeping the temperature below 70° C. to a crudeoil to remove traces of ethyl acetate. The residue was diluted intoluene (6.9 L, 1.5 vol) and added to n-hexane (138 L, 30 vol) withstirring at 25-35° C. After 1 to 2 hr, the mass was filtered throughcelite (4.6 kg) and the celite bed was washed with mixture of tolueneand hexane (1:10, 0.92 L, 0.2 vol toluene and 9.2 L, 2 vol hexane)followed by hexane washing (46 L, 10 vol). The combined filtrate wasstirred with silica gel (6.9 kg, 1.5 wt) for 1.5 to 2.5 hr at 25-35° C.Silica gel was filtered off and filtered silica gel was washed with amixture of hexane and triethylamine (20:1 mixture, 5×48.3 L). Thecombined filtrate was then concentrated twice in vacuo (vacuum not lessthan 600 mm Hg) keeping the temperature below 70° C. Toulene (4.6 L, 1vol) was then added to the residue (approximately 10 L) and againconcentrated in vacuo (vacuum not less than 650 mm Hg) keeping thetemperature below 70° C. to remove traces of solvent (toluene less than10%). The residue was cooled, unloaded and stored under nitrogen. Thetitle compound was obtained in 82.5% yield (4.25 kg) and in 99.0%purity.

¹H NMR (400 MHz, CDCl₃) δppm/TMS 0.95 (3H, t), 1.4 (2H, m), 1.7 (2H, m),2.75 (2H, q), 7.25 (1 H, m), 7.4 (2H, m—partly obscured by CHCl₃), 8.1(1 H, d), 8.9 (1 H, d)

Intermediate 4 (Stages 2a and 2b) 6-Butyl-8-(4-piperidinyloxy) quinoline

Under a nitrogen atmosphere, N-Boc-4-hydroxypiperidine (commerciallyavailable, for example, from Aldrich) (11.66 kg, 1.5 eqv) and sodiumPert-butoxide (5.5 kg, 1.5 eqv) was charged into a reactor containingN-methylpyrrolidinone (39.25 L, 5 vol) and stirred at approximately 25°C. to obtain a clear solution. In another reactor under a nitrogenatmosphere was charged 6-butyl-8-fluoroquinoline (for example, asobtained from Stage 1) (7.85 kg, 1.0 eqv) and N-methylpyrrolidinone(31.4 L, 4 vol) under nitrogen and heated to approximately 110° C. over1-3 hr. From the first reactor, the solution ofN-Boc-4-hydroxypiperidine sodium salt in N-methylpyrrolidinone was addedslowly over 2-3 hr into the second reactor containing6-butyl-8-fluoroquinoline in N-methylpyrrolidinone at approximately 110°C. The reaction mixture was stirred for approximately 1 hr atapproximately 110° C. and progress of the reaction was monitored by HPLC(starting material not more than 2%). After completion of reaction, thetemperature was adjusted to 30-40° C. and a saturated solution ofammonium chloride (7.85 kg ammonium chloride in 157 L water, 20 vol) wasadded into the reaction mass below 40° C. To this reaction mixture,ethyl acetate (78.5 L, 10 vol) was added followed by acetic acid (1.15L, 0.15 vol) and stirred well. The organic layer was separated, andaqueous layer was again extracted with ethyl acetate (39.25 L, 5 vol).The combined organics were then washed with water (78.5 L, 10 vol×3).The combined organics were concentrated in vacuo (vacuum not less than600 mm Hg), keeping the temperature below 60° C. To the concentratedreaction mass, toluene (23.55 L, 3 vol) was added, and the reactionmixture concentrated in vacuo (vacuum not less than 600 mm Hg), keepingthe temperature below 60° C. To this crude mass again fresh toluene(78.5 L, 10 vol) was added, followed by 22.8% HCl in iso-propyl alcohol(24.51 L, 3.36 eqv), and reaction mixture was stirred at 70-80° C. for1-2 hr. The progress of the reaction was monitored by HPLC (startingmaterial less than 2% by HPLC). After completion of reaction, thereaction was cooled to 30-40° C. and water (78.5 L, 10 vol) was addedportionwaise into the reaction mixture, stirred well and the layersseparated. The aqueous layer was washed three times with dichloromethane(78.5 L, 10 vol, then 54.95 L, 7 vol, then 39.25 L, 5 vol). The aqueouslayer was slowly basified with sodium hydroxide solution (7.85 kg in54.95 L water) until pH was 12.5 to 13.5. The product was extracted indichloromethane (78.5 L, 10 vol, then 39.25 L, 5 vol, x 2). The combineddichloromethane layers were washed with aqueous sodium chloride solution(7.85 kg in 78.5 L water, x 3). The combined organics were concentratedin vacuo (vacuum no less than 600 mm Hg) keeping the temperature below50° C. In order to remove traces if dichloromethane,N,N′-dimethylformamide (23.6 L, 3 vol) was added and the reaction masswas held at a vacuum of no less than 650 mm Hg, keeping the temperaturebelow 50° C. The title compound (3.76 kg, 34.24% yield) was obtained assolution in N,N′-dimethylformamide and stored at approximately 5° C.

¹H NMR (400 MHz, CDCl₃) δppm/TMS 0.95 (3H, t), 1.4 (2H, m), 1.7 (2H, m),1.9 (2H, m), 2.2 (2H, dd), 2.75 (2H, m), 2.85 (2H, m), 3.3 (2H, m), 4.7(1H, m), 7.0 (1H, s), 7.2 (1H, s), 7.35 (1H, m), 8.05 (1H, m), 8.85 (1H,d)

Intermediate 45 (Stages 3a and 3b)4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)butyl ethanesulfonate

To a solution of 4-aminobutanol (commercially available, for example,from Aldrich) (2.6 kg, 1 eqv) in toluene (65 L, 25 vol) at 25-35° C. wasadded phthalic anhydride (commercially available, for example, fromAldrich) (4.3 kg, 1 eqv). The temperature of the reaction mixture wasslowly raised to 80-90° C. for 2-3 hr and then heated to reflux toazeotropically remove the water from the reaction mass. The progress ofthe reaction was monitored by TLC, and after passing the TLC (startingmaterial not more than 2%), approximately 25-40% of toluene was removedfrom reaction by atmospheric distillation. The reaction mass was thencooled to 0-5° C. and triethylamine (4.4 kg, 1.5 eqv) was charged to thereaction mass over 15 min. Ethane sulphonyl chloride (commerciallyavailable, for example, from Aldrich) (4.5 kg, 1.2 eqv) diluted intoluene (7.8 L, 3 vol) was slowly added into the reaction mass at 0-5°C. under a nitrogen atmosphere. The reaction mixture was stirred forapproximately 2 hr, then monitored by HPLC (starting material not morethan 2%). After completion of reaction, water (26 L, 10 vol) andtriethylamine (2.6 kg, 1 vol) was added to the reaction mass, andstirred at 30-35° C. for 10-30 min, and then filtered over celite (1.3kg, 0.5 wt, pre-conditioned with toluene, 2.6 L, 1 vol). The celite wasthen washed with hot toluene (40-50° C., 10.4 L, 4 vol), and the organiclayer was separated. The aqueous layer was extracted with toluene (7.8L, 3 vol) and combined organic layers were then washed with aqueoussodium bicarbonate solution (2.6 kg in 26 L water) and water (13 L, 5vol). The organic layer was concentrated in vacuo (vacuum no less than600 mm Hg), keeping the temperature below 70° C. Iso-propylalcohol (7.8L, 3 vol) was added and the reaction mass was concentrated in vacuo(vacuum no less than 600 mm Hg), keeping the te,perature below 70° C. Tothis concentrated mass, iso-propylalcohol (26 L, 10 vol) was added, andwarmed to 50-60° C. to give a clear solution. This solution was cooledto 35-45° C. and n-hexane (26 L, 10 vol) was added slowly and thencooled to 25-35° C. The reaction mass was stirred for 1.5 to 2.5 hr andfiltered by centrifugation. The wet cake was washed with n-hexane (31 L,11.9 vol) and filtered again by centrifugation. The material was driedin vacuo (vacuum no less than 650 mm Hg) for 10-12 hr at 50-55° C. Thetitle compound was isolated in 78.36% yield (7.1 kg) and 99.6% purity.

¹H NMR (400 MHz, CDCl₃) δppm/TMS 1.4 (3H, t), 1.8 (4H, m), 3.15 (2H, m),3.7 (2H, m), 4.25 (2H, m), 7.75 (2H, m), 7.85 (2H, m)

Intermediate 37 (Stages 4a and 4b)4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)amine

To a solution of 6-butyl-8-(4-piperidinyloxy)quinoline (for example, asprepared for Intermediate 4 in stages 2a and 2b) (3.76 kg, 1 eqv) inN,N′-dimethylformamide (7.52 L, 2 vol) was added tetrabutylammoniumiodide (commercially available, for example, from Aldrich) (0.019 kg,0.005 wt), sodium iodide (1.98 kg, 1 eqv), diisopropylethylamine (3.42kg, 2 eqv), and 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)butylethanesulfonate (for example, as prepared for Intermediate 45 in stages3a and 3b) (4.32 kg, 1.1 eqv) under nitrogen atmosphere at 25-35° C. Thereaction mass was warmed to about 70-80° C. and maintained at thattemperature for 10-12 hr. The reaction was monitored by HPLC (startingmaterial not more than 1.5%). After the completion of reaction, thereaction mixture was cooled to 30-40° C. The reaction mixture wasdiluted with water (37.6 L, 10 vol) followed by toluene (37.6 L, 10vol). To the reaction mixture was then added activated carbon (0.38 kg,0.1 wt) and celite (0.94 kg, 0.25 wt) and warmed to 50-60° C. for 15-30min. The reaction mixture was stirred and cooled to 25-35° C., thenfiltered over celite (celite bed made with 1 kg celite, 18.8 L water, 5vol). The celite bed was then washed with hot (50-60° C.) toluene (18.8L, 5 vol). The combinted filtrates were separated and the aqueous layerwas extracted with toluene (18.8 L, 5 vol, ×3). The combined organiclayers were washed with water (37.6 L, 10 vol, ×3). The organic layerwas washed with concentrated [37.36%] aqueous HCl (22.56 L, 6 vol) andthe aqueous HCI layer containing product was collected. The aqueous HCIlayer was then heated to reflux (110-120° C.) and 5-10% of solvent wasdistilled off. Reflux was then continued for a further 10-12 hr. Analiquot of sample was submitted for HPLC (starting material not morethan 2%), then the reaction mixture was cooled to 5-15° C., stirred for30-60 min, filtered in vacuo and the filter cake was washed with cooled(5-15° C.) water (7.52 L, 2 vol). The resulting filtrate was basified byslow addition of sodium hydroxide solution (19.5 L NaOH solution [madewith 11.28 kg NaOH and 22.56 L water]) to pH 4-5. The aqueous layer wasthen washed with dichloromethane/iso-propylalcohol (10:1, 41.36 L, 11vol, then 20.68 L, 5.5 vol×2). The pH of the aqueous layer containingproduct was slowly adjusted to pH 8 to 9 keeping the temperature atappromiately 30° C. by adding sodium hydroxide solution (2 L NaOHsolution [made with 11.28 kg NaOH and 22.56 L water]). The aqueous layerwas then extracted with dichloromethane (37.6 L, 10 vol, then 18.8 L, 5vol, then 11.28 L, 3 vol), and the combined organics were washed with asolution of dilute ammonia (37.6 L ammonia solution [15.04 L ammonia(22.38%) and 22.56 L water]) and iso-propylalcohol (18.8 L, 5 vol),followed by dilute ammonia (37.6 L ammonia solution, [15.04 L ammonia(22.38%) and 22.56 L water]×2). 20-40% of dichloromethane solvent wasremoved by distillation at atmospheric pressure. The remaining mixturewas concentrated in vacuo (vacuum no less than 650 mm Hg), keeping thetemperature below 40-45° C. The residue was diluted with dichloromethane(1.88 L, 0.5 vol) and can be stored under nitrogen at 2-8° C. for up to3 days. The title compound was isolated in 56.68% yield (2.57 kg) and86% purity.

¹H NMR (400 MHz, CDCl₃) δ ppm/TMS 0.95 (3H, t), 1.4 (2H, m), 1.5 (4H,m), 1.7 (2H, m), 2.05 (2H, m), 2.2 (2H, m), 2.3 (2H, m), 2.4 (2H, m),2.75 (4H, m), 2.95 (2H, m), 4.6 CI H, m), 6.95 (1H, s), 7.2 (1H, s),7.35 (1H, d), 8.0 (1H, d), 8.85 (1H, d)

Example 23B (Stage 5)N-(4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide,dihydrochloride salt

To a solution of4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)amine (for example,as prepared for Intermediate 37 in stages 4a and 4b) (2.57 kg, 1.0 eqv)was added dichloromethane (30.84 L, 12 vol), and triethylamine (2.05 kg,2.8 eqv) under a nitrogen atmosphere. The reaction mixture was cooled to0-5° C. and a solution of ethanesulphonyl chloride (commerciallyavailable, for example, from Aldrich) (1.86 kg, 2.0 eqv) indichloromethane (7.71 L, 3 vol) was added dropwise at 0-10° C. Afterstirring for 2-3 hr at 0-10° C. under nitrogen, the reaction temperaturewas adjusted to 25-35° C. and stirred for 2-3 hr. A sample was analysedby HPLC to monitor reaction progress. The reaction mixture was quenchedat 25-35° C. with water (25.7 L, 10 vol). The organic layer wasseparated and the aqueous layer extracted with dichloromethane (7.71 L,3 vol). The combined organics were washed with citric acid solution(5.14 kg, 2 wt dissolved in 25.7 L water, 10 vol). The aqueous layercontaining product was collected and the organic layer was again washedwith aqueous citric acid solution (0.77 kg, 0.3 wt, dissolved in 3.34 Lwater, 1.3 vol) and the organic layer was separated. The combinedaqueous layers were washed with dichloromethane (12.8 L, 5 vol). Diluteammonia solution (12.85 L ammonia (22.38%) dissolved in 12.85 L water)was then added to the aqueous layer keeping the temperature at 30-35°C., until the pH reached was between 10-12. The product from the aqueouslayer was then extracted with dichloromethane (25.7 L, 10 vol, then7.71, 3 vol) and the combined organics were again washed with diluteammonia solution (5.14 L ammonia (22.38%) dissolved in 5.14 L water).The organic layer was finally washed twice with water (25.7 L, 10 vol)then 50-80% solvent was removed by distillation under atmosphericpressure, keeping the temperature below 55° C. The reaction mixture wasthen concentrated in vacuo (vacuum no less than 600 mm Hg) keeping thetemperature below 50° C. To this crude mixture, iso-propylalcohol (7.71L, 3 vol) was added and concentrated in vacuo (vacuum no less than 600mm Hg) keeping the temperature below 50° C. To this, methanol (17.99 L,7 vol) and activated carbon (0.13 kg, 0.05 wt) were added sequentially,and stirred for 15-30 min. The charcoal was filtered over a celite bed(prepared using 1.5 kg celite and 7.71 L methanol), then washed withmethanol (7.71 L, 3 vol) and to the combined filtrate, HCl iniso-propylalcohol (22.8%, 3.6 L, 2.65 eqv) was added at 20-30° C., andstirred for 15-30 min. The reaction mass was then concentrated in vacuo(vacuum no less than 650 mm Hg) until a syrup remained which started tosolidify, then methanol (12.85 L, 5 vol) was added to the residue toobtain a clear solution. The reaction mass was then stirred at 30-35°C., and ethyl acetate (51.4 L, 20 vol) was added. The reaction mass wasthen stirred for 1-2 hr at 25-35° C. and then cooled to 5-10° C. for 1-2hr, then centrifuged. The solid was then washed with methanol:ethylacetate mixture (1:7, 2.57 L methanol in 17.99 L ethyl acetate) at 5-10°C. and centrifuged. The product was dried in vacuo (vacuum no less than650 mm Hg) at 50-55° C. for 8-12 hrs. The title compound was obtained in53.15% yield (2 kg).

¹H NMR (400 MHz, CDCl₃) δ ppm/TMS 0.95 (3H, t), 1.4 (5H, m), 1.7 (4H,m), 2.1 (2H, m), 2.2 (2H, d), 2.9 (4H, m), 3.0 (2H, m), 3.2 (2H, m), 3.5(4H, m), 4.4 (2H, broad s), 5.3 (1H, s), 6.4 (1H, s), 7.4 (1H, s), 7.5(1H, s), 7.95 (1H, d), 8.8 (1H, d), 9.3 (1H, s), 11.3 (1H, s), 17.1 (1H,s)

Recrystallisation ofN-(4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide, dihydrochloride salt (Example 23B, Stage 6)

A solution ofN-(4-{-4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide,dihydrochloride salt (for example, as prepared for Example 23B in stage5) (2 kg, 1 eqv) in methanol (8 L, 4 vol) at 25-35° C. was passedthrough catridge filters (1 micron, followed by 0.2 micron frit) and theline flushed with methanol (2 L, 1 vol). The filtrate was cooled to25-30° C. and stirred for 30 min to ensure complete dissolution. Ethylacetate (4.4 L, 2.2 vol) was slowly added into the reaction mixture,which was then seeded withN-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide,dihydrochloride salt (0.0048 kg, 0.0024 wt) and aged isothermally for30-45 min at 25-30° C. Further ethyl acetate (35.6 L, 17.8 vol) wasadded slowly over 2-2.5 hr, keeping the temperature between 25-30° C.,then stirred at this temperature for 30 min. The reaction mixture wasslowly cooled to 0-10° C., and stirred at this temperature for anadditional 2-3 hrs. The product was filtered through a centrifuge andwashed with pre-chilled (0-10° C.) ethyl acetate (4 L, 2 vol). The cakewas offloaded, spin-dried then dried in vacuo (vacuum no less than 600mm Hg) at 55-60° C. for 12-14 hrs to give the title compound in 85.55%yield (1.72 kg) and 98.59% purity.

An XRPD pattern ofN-(4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide,dihydrochloride salt (as prepared for Example 23B) is shown in FIG. 1and FIG. 2. The peak angles and d-spacings for this form are tabulatedbelow:

Two theta (°) d-spacing ({acute over (Å)}) 10.3 8.6 12.5 7.1 15.5 5.720.7 4.3 23.0 3.9 24.9 3.6 27.6 3.2

Example 24N-(4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)-1-propanesulfonamide,dihydrochloride salt

(4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)amine (forexample, as prepared for Intermediate 37) (36 mg, 0.1 mmol) wasdissolved in DCM (2 ml) with stirring, and treated with triethylamine(22 μl, 0.16 mmol), and 1-propanesulfonyl chloride (commerciallyavailable, for example, from Aldrich) (14 μl, 0.12 mmol). The mixturewas stirred at room temperature for 1 h. The mixture was washed withsaturated aqueous sodium hydrogen carbonate, and the aqueous layer wasextracted with further DCM (×2) (hydrophobic frit). The combined organicsolutions were concentrated, and the residue was purified by MDAP. Theappropriate fractions were combined and concentrated to give the titlecompound as the formate salt: LCMS RT=2.89 min, ES+ve m/z 462 (M+H)⁺.The material was dissolved in methanol and treated with 1.25 M hydrogenchloride in methanol (0.6 ml, excess). The volatiles were removed invacuo to give the title compound (17 mg 32%): LCMS RT=2.88 min, ES+vem/z 462 (M+H)⁺.

Example 25N-(4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)-2-propanesulfonamide,dihydrochloride salt

(4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)amine (forexample, as prepared for Intermediate 37) (87 mg, 0.24 mmol) wasdissolved in DCM (2 ml), and treated with triethylamine (167 μl, 1.2mmol), and 2-propanesulfonyl chloride (commercially available, forexample, from Aldrich) (54 μl, 0.48 mmol). The mixture was stirred atroom temperature for 1.5 h. LCMS analysis indicated that reaction wasnot complete. Further triethylamine (167 μl, 1.2 mmol), and2-propanesulfonyl chloride (54 μl, 0.48 mmol) were added and the mixturestirred at room temperature for 1 h. The reaction was quenched by theaddition of methanol then concentrated under a stream of nitrogen. Theresidue was re-dissolved in methanol and applied to an SCX-2 cartridge(20 g) eluting with methanol, followed by 10% aqueous 0.88 s.g. ammoniain methanol. The relevant fractions were concentrated, and the residuewas purified by MDAP. The appropriate fractions were combined andconcentrated, but the product was found to contain impurities, thoughtto be (3-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)sulfamicacid. The material was dissolved in methanol and applied to anaminopropyl cartridge (5 g) eluting with methanol. The relevantfractions were combined and concentrated to give the title compound asthe free base (43 mg, 39%): LCMS RT=2.63 min, ES+ve m/z 462 (M+H)⁺.Approximately half the material was dissolved in methanol and treatedwith 1.25 M hydrogen chloride in methanol (1 ml, excess). The volatileswere removed under a stream of nitrogen to give the title compound (26mg): LCMS RT=2.70 min, ES+ve m/z 462 (M+H)⁺.

Example 26N-(4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)-2-methyl-1-propanesulfonamide,dihydrochloride salt

(4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)amine (forexample, as prepared for Intermediate 37) (39 mg, 0.11 mmol) wasdissolved in DCM (2 ml) with stirring, and treated with triethylamine(25 μl, 0.18 mmol), and isobutanesulfonyl chloride (commerciallyavailable, for example, from Aldrich) (17 μl, 0.13 mmol). The mixturewas stirred at room temperature for 1 h, then treated with furthertriethylamine (13 μl, 0.09 mmol), and isobutanesulfonyl chloride (13 μl,0.10 mmol). The mixture was stirred at room temperature for a further 30min. The mixture was washed with saturated aqueous sodium hydrogencarbonate, and the aqueous layer was extracted with further DCM (×2)(hydrophobic frit). The combined organic solutions were concentrated,and the residue was purified by MDAP. The appropriate fractions werecombined and concentrated to give the title compound as the formatesalt: LCMS RT=3.05 min, ES+ve m/z 476 (M+H)⁺. The material was dissolvedin methanol and treated with 1.25 M hydrogen chloride in methanol (0.6ml, excess). The volatiles were removed under a stream of nitrogen togive the title compound (11 mg, 18%):

LCMS RT=3.02 min, ES+ve m/z 476 (M+H)⁺.

Example 27N-(4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)cyclohexanesulfonamide,dihydrochloride salt

(4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)amine (forexample, as prepared for Intermediate 37) (74 mg, 0.2 mmol) wasdissolved in DCM (2 ml), and treated with triethylamine (55 μl, 0.4mmol), and cyclohexanesulfonyl chloride (commercially available, forexample, from Aldrich) (44 μl, 0.30 mmol). The mixture was stirred atroom temperature for 1 h. LCMS analysis indicated that reaction was notcomplete. Further triethylamine (55 μl, 0.4 mmol), andcyclohexanesulfonyl chloride (20 ml, 0.1 mmol) were added and themixture stirred at room temperature for overnight. The reaction wasquenched by the addition of methanol then concentrated under a stream ofnitrogen. The residue was re-dissolved in methanol and applied to anSCX-2 cartridge (20 g) eluting with methanol, followed by 10% aqueous0.88 s.g. ammonia in methanol. The relevant fractions were concentrated,and the residue was purified by MDAP. The appropriate fractions werecombined and concentrated to give the title compound as the formatesalt: LCMS RT=3.08 min, ES+ve m/z 502 (M+H)⁺. The material was dissolvedin methanol and treated with 1.25 M hydrogen chloride in methanol (0.5ml, excess). The volatiles were removed under a stream of nitrogen togive the title compound (26 mg, 23%): LCMS RT=3.06 min, ES+ve m/z 502(M+H)⁺.

Example 28N-(4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)-1-cyclohexylmethanesulfonamide, dihydrochloride salt

This was prepared in an analogous manner to that disclosed for Example24 using (4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)amine(for example, as prepared for Intermediate 37) (42 mg, 0.12 mmol),triethylamine (26 p1, 0.19 mmol), and cyclohexylmethanesulfonyl chloride(commercially available, for example, from Array Biopharma) (39 mg, 0.20mmol) in DCM (2 ml). The title compound was initially obtained as theformate salt, but required further purification. The salt wasre-dissolved in methanol and applied an SCX-2 cartridge (5 g) elutingwith methanol, followed by 10% aqueous 0.88 s.g. ammonia in methanol.The relevant basic fractions were concentrated in vacuo to provide thetitle compound as the free base: LCMS RT=3.31 min, ES+ve m/z 516 (M+H)⁺.The material was dissolved in methanol and treated with 1.25 M hydrogenchloride in methanol (1 ml, excess). The volatiles were removed under astream of nitrogen to give the title compound (26 mg, 37%):

LCMS RT=3.29 min, ES+ve m/z 516 (M+H)⁺.

Example 29N-(4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)-N-methylethanesulfonamide,dihydrochloride salt

DMF (0.5 ml) was added to sodium hydride (60% dispersion in oil, 20 mg,0.5 mmol) and the mixture was stirred under nitrogen at roomtemperature.N-(4-{-4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide(for example, as prepared for Example 23, preparation A) (56 mg, 0.125mmol) was added as a solution in DMF (2 ml), and the mixture stirred for10 min. Methyl iodide (commercially available, for example, fromAldrich) (17 mg, 0.125 mmol) was added as a solution in DMF (200 μl),and the reaction was stirred under nitrogen at room temperature for 1.5h. The mixture was diluted with methanol and applied to an SCX-2cartridge (50 g) eluting with methanol, followed by 10% aqueous 0.88s.g. ammonia in methanol. The relevant fractions were concentrated, andthe residue was purified by MDAP. The appropriate fractions werecombined and concentrated to give the title compound as the formatesalt: LCMS RT=2.68 min, ES+ve m/z 462 (M+H)⁺. The material was dissolvedin methanol and treated with 1.25 M hydrogen chloride in methanol (0.5ml, excess). The volatiles were removed under a stream of nitrogen togive the title compound (35 mg, 52%): LCMS RT=2.76 min, ES+ve m/z 462(M+H)⁺.

Example 30

N-(4-{4-[(6-Pentyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide,dihydrochloride salt

A mixture of 6-pentyl-8-(4-piperidinyloxy)quinoline (for example, asprepared for Intermediate 8) (62 mg, 0.2 mmol) and4-[(ethylsulfonyl)amino]butyl ethanesulfonate (for example, as preparedfor Intermediate 40) (80 mg, 0.24 mmol), sodium hydrogen carbonate (120mg, 1.4 mmol) and sodium iodide (29 mg, 0.19 mmol) in DMF (2 ml) washeated to 150° C. for 15 min in a Smith Creator™ microwave oven. LCMSanalysis showed that reaction was incomplete, so further4-[(ethylsulfonyl)amino]butyl ethanesulfonate (26 mg, 0.1 mmol) and DMF(0.5 ml) were added and the mixture was heated for 15 min further at150° C. in a Smith Creator™ microwave oven. LCMS analysis showed thatreaction was still incomplete, so the mixture was transferred to aflask, diluting with further DMF (2 ml). Further4-[(ethylsulfonyl)amino]butyl ethanesulfonate (80 mg, 0.29 mmol) and DMF(1 ml) were added and the mixture was heated to 60° C. for 3 h undernitrogen. Further 4-[(ethylsulfonyl)amino]butyl ethanesulfonate (82 mg,0.3 mmol), sodium iodide (60 mg, 0.4 mmol) and DMF (1 ml) were added andthe mixture was heated to 60° C. overnight under nitrogen. The reactionmixture was concentrated in vacuo. The residue was applied to an SCX-2cartridge (20 g) eluting with methanol, followed by 10% aqueous 0.88s.g. ammonia in methanol. The relevant fractions were concentrated, andthe residue was purified by MDAP. The appropriate fractions werecombined and concentrated to give the title compound as the formatesalt: LCMS RT=2.92 min, ES+ve m/z 462 (M+H)⁺. The material was dissolvedin methanol and treated with 1.25 M hydrogen chloride in methanol (0.5ml, excess). The volatiles were removed under a stream of nitrogen togive the title compound (15 mg, 14%): LCMS RT=2.95 min, ES+ve m/z 462(M+H)⁺.

Example 31N-(5-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}pentyl)methanesulfonamide,dihydrochloride salt

This was prepared in an analogous manner to that disclosed for Example24 using (5-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}pentypamine(for example, as prepared for Intermediate 38) (35 mg, 0.1 mmol),triethylamine (22 μl, 0.16 mmol), and methanesulfonyl chloride(commercially available, for example, from Aldrich) (9 μl, 0.12 mmol) inDCM (2 ml). The title compound was obtained as the formate salt: LCMSRT=2.71 min, ES+ve m/z 448 (M+H)⁺.

The material was dissolved in methanol and treated with 1.25 M hydrogenchloride in methanol (0.5 ml, excess). The volatiles were removed undera stream of nitrogen to give the title compound (32 mg, 61%); LCMSRT=2.71 min, ES+ve m/z 448 (M+H)⁺.

Example 32 N-(5-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}pentyl)ethanesulfonamide,dihydrochloride salt

This was prepared in an analogous manner to that disclosed for Example24 using (5-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}pentyl)amine(for example as prepared for Intermediate 38) (44 mg, 0.12 mmol),triethylamine (27 μl, 0.19 mmol), and ethanesulfonyl chloride(commercially available, for example, from Aldrich) (14 μl, 0.14 mmol)in DCM (2 ml). The title compound was obtained as the formate salt: LCMSRT=2.79 min, ES+ve m/z 462 (M+H)⁺. The material was dissolved inmethanol and treated with 1.25 M hydrogen chloride in methanol (0.5 ml,excess). The volatiles were removed under a stream of nitrogen to givethe title compound (38 mg, 59%); LCMS RT=2.78 min, ES+ve m/z 462 (M+H)⁺.

Example 332-{(4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}-N-(1,1-dimethylethyl)ethanesulfonamide,formate salt (1:1)

This was prepared in an analogous manner to that disclosed for Example34 using a mixture of N-(1,1-dimethylethyl)ethenesulfonamide and2-chloro-N-(1,1-dimethylethyl)ethane sulfonamide (for example, asprepared for Intermediate 42) (1:1), yield 4%. LCMS RT=2.95 min, ES+vem/z 448 (M+H)⁺.

Example 343-{(4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}-N-(1,1-dimethylethyl)-1-propanesulfonamide,dihydrochloride salt

To a solution of 6-butyl-8-(4-piperidinyloxy)quinoline (for example, asprepared for Intermediate 4) (0.24 g, 0.84 mmol) in DMF (5 ml) was addedsodium iodide (0.22 g, 1.5 mmol), potassium carbonate (0.21 g, 1.5 mmol)and then 3-chloro-N-(1,1-dimethylethyl)-1-propanesulfonamide (forexample, as prepared for Intermediate 41) (0.32 g, 1.50 mmol). Theslight suspension was heated to 60° C. for 6 h. The mixture was appliedto an SCX-2 cartridge (20 g), preconditioned with methanol, and thecartridge washed with methanol (2 column volumes). The cartridge waseluted with 10% 0.880 s.g. ammonia in methanol (2 column volumes) andthe basic fractions concentrated in vacuo. The residue (0.36 g) waspurified by MDAP and the appropriate fractions combined. The solvent wasremoved in vacuo to give the formate salt of the title compound (142 mg,33%): LCMS RT=2.90 min, ES+ve m/z 462 (M+H)⁺. A portion of the formatesalt (47 mg, 0.092 mmol) in methanol (1.5 ml) was treated with 1.25 Mhydrogen chloride in methanol (0.5 ml, 0.6 mmol). The solvent wasremoved using a stream of nitrogen to give the title compound as ayellow solid (49 mg).

LCMS RT=2.95 min, ES+ve m/z 462 (M+H)⁺.

Example 354-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}-N-propyl-1-butanesulfonamide,formate salt (1:1)

This was prepared in an analogous manner to that disclosed for Example34 using 4-chloro-N-propyl-1-butanesulfonamide (for example, as preparedfor Intermediate 43). Yield 5%.

LCMS RT=2.92 min, ES+ve m/z 462 (M+H)⁺.

Example 36N-(3-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)-N′-propylurea,dihydrochloride salt

(3-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)amine (forexample, as prepared for Intermediate 36) (33 mg, 0.1 mmol) wasdissolved in DCM (2 ml), and treated with propyl isocyanate(commercially available, for example, from Aldrich) (14 μl, 0.15 mmol).The mixture was stirred at room temperature for 20 min, then left tostand at room temperature overnight. The reaction mixture was applied toan SCX-2 cartridge (10 g) eluting with methanol, followed by 10% aqueous0.88 s.g. ammonia in methanol. The relevant fractions were concentrated,and the residue was purified by MDAP. The appropriate fractions werecombined and concentrated to give the title compound as the formate salt(34 mg): LCMS RT=2.76 min, ES+ve m/z 427 (M+H)⁺. The material wasdissolved in methanol and treated with 1.25 M hydrogen chloride inmethanol (0.5 ml, excess). The volatiles were removed under a stream ofnitrogen to give the title compound (40.5 mg, 81%): LCMS RT=2.78 min,ES+ve m/z 427 (M+H)⁺.

Biological Assays

The compounds of the invention may be tested for in vitro and/or in vivobiological activity in accordance with the following or similar assays.

H1 Receptor Cell Line Generation and FLIPR Assay Protocol 1. Generationof Histamine H1 Cell Line

The human H1 receptor is cloned using known procedures described in theliterature [Biochem. Biophys. Res. Commun., 201(2):894 (1994)]. Chinesehamster ovary (CHO) cells stably expressing the human H1 receptor aregenerated according to known procedures described in the literature [Br.J. Pharmacol., 117(6):1071 (1996)].

Histamine H1 Functional Antagonist Assay: Determination of FunctionalpKi Values

The histamine H1 cell line is seeded into non-coated black-walled clearbottom 384-well tissue culture plates in alpha minimum essential medium(Gibco/Invitrogen, cat no. 22561-021), supplemented with 10% dialysedfoetal calf serum (Gibco/Invitrogen cat no. 12480-021) and 2 mML-glutamine (Gibco/Invitrogen cat no 25030-024) and is maintainedovernight at 5% CO₂, 37° C.

Excess medium is removed from each well to leave 10 μl. 30 μl loadingdye (250 μM Brilliant Black, 2 μM Fluo-4 diluted in Tyrodesbuffer+probenecid (145 mM NaCl, 2.5 mM KCl, 10 mM HEPES, 10 mMD-glucose, 1.2 mM MgCl₂, 1.5 mM CaCl₂, 2.5 mM probenecid, pH adjusted to7.40 with NaOH 1.0 M)) is added to each well and the plates areincubated for 60 min at 5% CO₂, 37° C.

10 μl of test compound, diluted to the required concentration in Tyrodesbuffer+probenecid (or 10 μl Tyrodes buffer+probenecid as a control) isadded to each well and the plate is incubated for 30 min at 37° C., 5%CO₂. The plates are then placed into a FLIPR™ (Molecular Devices, UK) tomonitor cell fluorescence (λ_(ex)=488 nm, μ_(EM)=540 nm) in the mannerdescribed in Sullivan et al., (In: Lambert DG (ed.), Calcium SignalingProtocols, New Jersey: Humana Press, 1999, 125-136) before and after theaddition of 10 μl histamine at a concentration that results in the finalassay concentration of histamine being EC₈₀.

Functional antagonism is indicated by a suppression of histamine inducedincrease in fluorescence, as measured by the FLIPR™ system (MolecularDevices). By means of concentration effect curves, functional affinitiesare determined using standard pharmacological mathematical analysis.

Histamine H1 Functional Antagonist Assay: Determination of AntagonistpA2 and Duration

The histamine H1 receptor expressing CHO cells are seeded intonon-coated black-walled clear bottom 96-well tissue culture plates asdescribed above.

Following overnight culture, growth medium is removed from each well,washed with 200 μl PBS and is replaced with 50 μl loading dye (250 μMBrilliant Black, 1 μM Fluo-4 diluted in Tyrodes buffer+probenecid (145mM NaCl, 2.5 mM KCl, 10 mM HEPES, 10 mM D-glucose, 1.2 mM MgCl₂, 1.5 mMCaCl₂, 2.5 mM probenecid, pH adjusted to 7.40 with NaOH 1.0 M)). Cellsare incubated for 45 min at 37° C. The loading buffer is removed and thecells are washed as above, and 90 p. 1 of Tyrodes buffer+probenecid isadded to each well. 10 μl of test compound, diluted to the requiredconcentration in Tyrodes buffer+probenecid (or 10 μl Tyrodesbuffer+probenecid as a control) is added to each well and the plate isincubated for 30 min at 37° C., 5% CO₂.

The plates are then placed into a FLIPR™ (Molecular Devices, UK) tomonitor cell fluorescence (λ_(ex)=488 nm, λ_(EM)=540 nm) in the mannerdescribed in Sullivan et al., (In: Lambert DG (ed.), Calcium SignalingProtocols, New Jersey: Humana Press, 1999, 125-136) before and after theaddition of 50 μl histamine over a concentration range of 1 mM -0.1 nM.The resultant concentration response curves are analysed by non-linearregression using a standard four parameter logistic equation todetermine the histamine EC₅₀, the concentration of histamine required toproduce a response of 50% of the maximum response to histamine. Theantagonist pA2 is calculated using the following standard equation:pA2=log(DR-1)−log[B] where DR=dose ratio, defined as EC₅₀antagonist-treated/EC₅₀ control and [B]=concentration of antagonist.

To determine the antagonist duration, cells are cultured overnight innon-coated black-walled clear bottom 96-well tissue culture plates, arewashed with PBS and are incubated with a concentration of antagonistchosen to give an approximate DR in the range 30-300. Following the 30min antagonist incubation period, the cells are washed two or threetimes with 200 μl of PBS and then 100 μl Tyrodes buffer is added to eachwell to initiate antagonist dissociation. Following incubation forpredetermined times, typically 30-270 min at 37° C., the cells are thenwashed again with 200 μl PBS and are incubated with 100 μl Tyrodesbuffer containing Brilliant Black, probenecid and Fluo-4 for 45 min at37° C., as described above. After this period, the cells are challengedwith histamine in the FLIPR™ as described above. The dose ratio at eachtime point is used to determine the fractional H1 receptor occupancy bythe following equation: fractional receptor occupancy=(DR-1)/DR. Thedecrease in receptor occupancy over time approximates to a straight lineand is analysed by linear regression. The slope of this straight linefit is used as an index of the dissociation rate of the antagonist. Thedose ratios for antagonist treated cells and for antagonist treated andwashed cells at each time point are used to calculate a relative doseratio (rel DR) which is also used as an index of antagonist duration.Antagonists with long duration of action produce rel DR values close to1, and antagonists with short duration of action produce rel DR valuesthat approaches the dose ratio value obtained for antagonist treatmentalone.

2. H3 Receptor Cell Line Generation, Membrane Preparation and FunctionalGTPγS Assay Protocols Generation of Histamine H3 Cell Line

The histamine H3 cDNA is isolated from its holding vector, pcDNA3.1 TOPO(InVitrogen), by restriction digestion of plasmid DNA with the enzymesBamH1 and Not-1 and is ligated into the inducible expression vectorpGene (InVitrogen) digested with the same enzymes. The GeneSwitch™system (a system where in transgene expression is switched off in theabsence of an inducer and switched on in the presence of an inducer) isperformed as described in U.S. Pat. Nos.: 5,364,791; 5,874,534; and5,935,934. Ligated DNA is transformed into competent DH5α E. coli hostbacterial cells and is plated onto Luria Broth (LB) agar containingZeocin™ (an antibiotic which allows the selection of cells expressingthe sh ble gene which is present on pGene and pSwitch) at 50 μgrml⁻¹.Colonies containing the re-ligated plasmid are identified by restrictionanalysis. DNA for transfection into mammalian cells is prepared from 250ml cultures of the host bacterium containing the pGeneH3 plasmid and isisolated using a DNA preparation kit (Qiagen Midi-Prep) as permanufacturers guidelines (Qiagen).

CHO K₁ cells previously transfected with the pSwitch regulatory plasmid(InVitrogen) are seeded at 2×10⁶ cells per T75 flask in Complete Medium,containing Hams F12 (GIBCOBRL, Life Technologies) medium supplementedwith 10% v/v dialysed foetal bovine serum, L-glutamine, and hygromycin(100 μgml⁻¹), 24 h prior to use. Plasmid DNA is transfected into thecells using Lipofectamine plus according to the manufacturer'sguidelines (InVitrogen). 48 h post transfection, cells are placed intocomplete medium supplemented with 500 μgml⁻¹ Zeocin™.

10-14 days post selection, 10 nM Mifepristone (InVitrogen) is added tothe culture medium to induce the expression of the receptor. 18 h postinduction, cells are detached from the flask using ethylenediaminetetra-acetic acid (EDTA; 1:5000; InVitrogen), following several washeswith PBS, pH 7.4 and are resuspended in Sorting Medium containingMinimum Essential Medium (MEM), without phenol red, and are supplementedwith Earles salts and 3% Foetal Clone II (Hyclone). Approximately 1×10⁷cells are examined for receptor expression by staining with a rabbitpolyclonal antibody, 4a, raised against the N-terminal domain of thehistamine H3 receptor, are incubated on ice for 60 min, followed by twowashes in sorting medium. Receptor bound antibody is detected byincubation of the cells for 60 min on ice with a goat anti rabbitantibody, conjugated with Alexa 488 fluorescence marker (MolecularProbes). Following two further washes with Sorting Medium, cells arefiltered through a 50 μm Filcon™ (BD Biosciences) and then are analysedon a FACS Vantage SE Flow Cytometer fitted with an Automatic CellDeposition Unit. Control cells are non-induced cells treated in ananalogous manner. Positively stained cells are sorted as single cellsinto 96-well plates, containing Complete Medium containing 500 μgml⁻¹Zeocin™ and are allowed to expand before reanalysis for receptorexpression via antibody and ligand binding studies. One clone, 3H3, isselected for membrane preparation.

Membrane Preparation from Cultured Cells

All steps of the protocol are carried out at 4° C. and with pre-cooledreagents. The cell pellet is resuspended in 10 volumes of homogenisationbuffer (50 mM N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid(HEPES), 1 mM ethylenediamine tetra-acetic acid (EDTA), pH 7.4 with KOH,supplemented with 10⁻⁶ M leupeptin (acetyl-leucyl-leucyl-arginal; SigmaL2884), 25 μgml⁻¹ bacitracin (Sigma B0125), 1 mM phenylmethylsulfonylfluoride (PMSF) and 2×10 M pepstain A (Sigma)). The cells are thenhomogenised by 2×15 second bursts in a 1 litre glass Waring blender,followed by centrifugation at 500 g for 20 min. The supernatant is thenspun at 48,000 g for 30 min. The pellet is resuspended in homogenisationbuffer (4× the volume of the original cell pellet) by vortexing for 5sec, followed by homogenisation in a Dounce homogeniser (10-15 strokes).At this point the preparation is aliquoted into polypropylene tubes andstored at −80° C.

Histamine H3 Functional Antagonist Assay For each compound beingassayed, in a solid white 384 well plate, is added:—(a) 0.5 μl of test compound diluted to the required concentration inDMSO (or 0.5 μl DMSO as a control);(b) 30 μl bead/membrane/GDP mix which is prepared by mixing Wheat GermAgglutinin Polystyrene LeadSeeker® (WGA PS LS) scintillation proximityassay (SPA) beads with membrane (prepared in accordance with themethodology described above) and diluting in assay buffer (20 mMN-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid (HEPES)+100 mMNaCl+10 mM MgCl₂, pH 7.4 NaOH) to give a final volume of 30 μl whichcontains 5 μg protein, 0.25 mg bead per well and 10 μM final assayconcentration of guanosine 5′ diphosphate (GDP) (Sigma, diluted in assaybuffer) incubating at room temperature for 60 min on a roller;(c) 15 μl 0.38 nM [³⁵S]-GTPγS (Amersham; Radioactivity concentration=37MBqml⁻¹; Specific activity=1160 Cimmol⁻¹), histamine (at a concentrationthat results in the final assay concentration of histamine being EC₈₀).

After 2-6 h, the plate is centrifuged for 5 min at 1500 rpm and countedon a Viewlux counter using a 613/55 filter for 5 minplate⁻¹. Data isanalysed using a 4-parameter logistic equation. Basal activity is usedas minimum, i.e. histamine not added to well.

Intranasal Challenge Method: Whole Body Plethysmography

(a)Sensitisation

Female Dunkin-Hartley guinea pigs 150-250 g are sensitised twice dailyfor 5 days (week 1) with ovalbumin (OVA) and aluminium hydroxide(Al(OH)₃ or Alum) in physiological saline, 25 μl/nostril. Solution ismade up at 20 μg/ml OVA, 180 mg/ml Alum. During weeks 2 and 3 animalsreceive 25 μl/nostril of OVA (5 mg/ml) once daily. During Week 4 guineapigs will be entered into study but are continually sensitized as perweeks 2 and 3 until the day before dosing with compound or vehicle.

(b) CompoundNehicle Pretreatment

Pretreatment with test compound is performed at various times prior tohistamine challenge. Efficacy dose-response curves are determined 1 hrand/or 3 hr after dosing whereas duration of action may be studied up to7 days post dose (for example, at 24 hours). Test compounds areformulated as solutions in 0.9% sterile saline or suspensions in 0.9%sterile saline/tween80.

Guinea pigs were anaesthetised with isoflurane (5%, 2-3 l/min O₂),placed in a supine position, and 25 μl of test compound or vehicle dosedinto each nostril using a Gilson pipette. After dosing, animals remainsupine for at least 30 seconds (e.g. 60 seconds) during recovery fromanaesthesia.

(c) Histamine Challenge Protocol

At 30 minutes before the time of histamine challenge, guinea pigs aredosed with atropine sulphate (Sigma A0257, dissolved in saline), 1 mg/kgi.p. Animals are then placed into whole body plethysmograph systems(Buxco® Electronics) where the parameter PenH area under curve (AUC) isrecorded as outlined in Hamelmann, E., Schwarze, J., Takeda, K., Oshiba,A., Larsen, L., Irvin, C. G. & Gelfand, E. W. (1997), Noninvasivemeasurement of airway responsiveness in allergic mice using barometricplethysmography., Am. J. Respir. Crit. Care Med., 156, 766-775. A 10minute baseline AUC is recorded and if this value is over 1000, theanimals are excluded.

After the stipulated pre-dose time has been reached, guinea pigs arere-anaesthetised with isoflurane and dosed with either 10 mM or 15 mMhistamine or phosphate-buffered saline (PBS), (25 μl per nostril). Onrecovery from anaesthesia animals are returned to the individualplethysmograph chambers and 4×10 min consecutive PenH AUC recordings aremade. These recordings are summed to give a cumulative AUC over 40 minspost histamine challenge for each animal. Data are analysed using ANOVAwith post-hoc Fishers LSD test (general linear models, Statistica®) andfinally Hochberg adjustment. Inhibition of histamine-induced congestionis determined by statistically significant differences between the meanresponses of compound pre-treated groups compared to the vehiclepre-treated, histamine-challenged group.

CNS penetration

(i) CNS Penetration by Bolus Administration

Compounds are dosed intravenously at a nominal dose level of 1 mgkg⁻¹ tomale CD Sprague Dawley rats. Compounds are formulated in 5% DMSO/45%PEG200/50% water. Blood samples are taken under terminal anaesthesiawith isoflurane at 5 min post-dose and the brains are also removed forassessment of brain penetration. Blood samples are taken directly intoheparinised tubes. Blood samples are prepared for analysis using proteinprecipitation and brain samples are prepared using extraction of drugfrom brain by homogenisation and subsequent protein precipitation. Theconcentration of parent drug in blood and brain extracts is determinedby quantitative LC-MS/MS analysis using compound-specific masstransitions.

(ii) CNS Penetration Following Intravenous Infusion at Steady State

A loading dose of the compounds is given to male CD Sprague Dawley ratsat a nominal dose level of 0.4 mgkg⁻¹. The compounds are then infusedintravenously for 4 h at a nominal dose level of 0.1 mgkg⁻¹h⁻¹.Compounds are formulated in 2% DMSO/30% PEG200/68% water. Serial orterminal blood samples are taken at 0.5, 1.5, 2.5, 3, 3.5 and 4 h postdose. The final blood sample is collected under terminal anaesthesiawith isoflurane and the brains are also removed for assessment of brainpenetration. Blood samples are taken directly into heparinised tubes.Blood samples are prepared for analysis using protein precipitation andbrain samples are prepared using extraction of drug from brain byhomogenisation and subsequent protein precipitation. The concentrationof parent drug in blood and brain extracts is determined by quantitativeLC-MS/MS analysis using compound-specific mass transitions.

Results

The compounds of Examples 1 to 36 were tested in the above or similarassays/methods and showed:

(i) Examples 1, 13, 14, 15 and 16 had an average pK_(i) (pK_(b)) at H1of approximately greater than 7. The remaining Examples had an averagepK_(i) (pK_(b)) at H1 of approximately greater than 8.Examples 8, 12 and 13 had average pA2 values of greater thanapproximately 7. Examples 1, 3, 9, 10, 14, 15, 16, 17, 25, 28, 29, 33and 35 had average pA2 values of greater than approximately 8. Examples2, 5, 6, 7, 11, 18, 19, 22, 23B, 24, 26, 31, 32, 34 and 36 had averagepA2 values of greater than approximately 9.(ii) The compounds of the Examples had an average pK_(i) (pK_(b)) at H3of less than 6.5.(iii) The compounds of Example 4A and Example 23B demonstrated low CNSpenetration.(iv) Compound of Examples 4B, 23, 24 and 26 exhibited at one or moretime points a longer duration of action than azelastine in the histamineH1 functional antagonist assay. Other compounds were either not testedor were tested and did not exhibit a longer duration* of action.(v) In the intranasal challenge model, compound of Example 23B dosedintranasally at 1 mg/ml either 3 hr or 24 hr before histamine challengesignificantly (p<0.05) inhibited the response at both timepoints. In thesame model, azelastine failed to show a similar duration of action whenadministered at the same concentration.

Example Compositions

The aqueous pharmaceutical compositions of the invention may be preparedaccording to the following general method:

Where appropriate, the isotonicity adjusting agent(s) is charged into asuitable mixing vessel containing purified water and dissolved withstirring.

The suspending/thickening agent(s) is then charged into the mixingvessel and dispersed throughout the solution. The resulting suspendingvehicle is allowed to hydrate for an appropriate period of time toensure cross-linkage and gelation, which may take 60 minutes or longer.

Preservative(s) is pre-dissolved in purified water in a separate vessel,optionally with heating, for example to 50-60° C. depending on thepreservative chosen, to aid dissolution, and then added to the thickenedisotonicity adjusting agent(s) solution with continuous stirring.

Buffering agents, if included, are dissolved in a minimum amount ofpurified water, optionally heated, for example to about 50-60° C. asappropriate depending on the buffering agents chosen, and stirred todissolve in separate containers. The separate solutions are combined,mixed well and then added to the bulk solution with continuous stirring.

In a separate mixing vessel, the wetting agent(s) is mixed with purifiedwater which optionally may be heated, for example to about 50-60° C. asappropriate depending on the wetting agent(s) chosen, and stirred todissolve. A slurry or solution of active compound(s) is then prepared byadding the resultant wetting agent(s) solution to the activecompound(s), which may be particle size reduced for example micronised,and mixed prior to homogenising/refining.

Additionally, in a separate mixing vessel, additional preservative(s),if needed, may be mixed with purified water and stirred to dissolve.

Following the dispersion and refining of the slurry/solution of activecompound(s) it is added to the mixing vessel containing thesuspending/thickening agent and dispersed with stirring. Following theaddition of the slurry of active compound(s), any additionalpreservative may be added to the bulk suspension/solution and dispersedwith continuous stirring. Finally, the suspension is made to its finalmass by adding water and stirred.

Co-solvent(s), if included, may be added before or after the addition ofthe buffering agents. Alternatively, the co-solvent(s) may be addedduring the formation of the drug slurry or solution.

Preservative(s), if included, may be added before or after the additionof the suspending/thickening agent(s).

Fluticasone furoate is used in its unsolvated form as polymorphicForm 1. The preparation of fluticasone furoate (6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-1,6-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester), solvates and polymorphs thereof includingpolymorphic Form 1, and biological activity thereof, are disclosed inInternational Patent Application WO02/12265 and International PatentApplication WO03/066024 incorporated fully herein by reference.

N-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamideis used in the form of the dihydrochloride salt, optionally aspolymorphic form 1.

Example Composition 1 May be Made According to the Following Procedure

Approximately 200 mL of water is added to a tared beaker. The xyltiol isadded with stirring (Silverson mixer) until dissolved. In a separatevessel, the EDTA is dissolved in approximately 5 mL, using heat (withoutboiling) to aid dissolution. The EDTA solution is then added to thexylitol solution. With mixing (Silverson mixer), the Avicel™ CL611 isadded to the xylitol and EDTA solution. The speed of the mixer isadjusted, as required, to maintain a vortex. After addition of theAvicel™ CL611, and once it is well dispersed, the mixture is allowed tostand for at least 60 minutes to ensure hydration of the Avicel™ CL611.In one vessel, the citric acid is dissolved in approximately 10 mL ofwater, and, in another vessel, the sodium citrate is dissolved in 10 mLof water. The vessels are heated with stirring (without boiling) to aiddissolution. Once the citric acid and sodium citrate are dissolved, theyare combined and mixed thoroughly. The buffer is then added to the bulksuspension with mixing (Silverson mixer). In another vessel, thepolysorbate 80 is dissolved in approximately 10 mL of water with heatand stirring (without boiling) to aid dissolution. The propylene glycolis added to the polysorbate 80 solution. ToN-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide(in the form of the dihydrochloride salt) is added approximately 3-5 mLof the propylene glycol and polysorbate 80 solution. The drug substanceis wetted by mixing with a spatula or alternatively placing in a sealedcontainer and shaking on a shaker until all the drug is wetted. The drugmixture is homogenised (small Silverson head or small Ultra Turrax) todisperse and/or dissolve the drug substance for approximately 2-3minutes. The drug mixture is added to the bulk suspension and mixed(Silverson mixer). Any remaining polysorbate 80 solution and propyleneglycol is added to the bulk suspension. The drug mixture vessel,polysorbate 80 vessel and propylene glycol vessel are rinsed with water(small Silveron head or Ultra Turrax) and the rinsings are added to thebulk solution. In another vessel, the potassium sorbate is dissolved inapproximately 5 mL of water with stirring and heat (without boiling) toaid dissolution. The potassium sorbate solution is added to the bulksolution with stirring (Silverson mixer). The tared beaker is made up tothe final weight with water (500 g) and mixed for a further 3 minutes.The pH is measured (target pH=4.5, with limits of 4.0 to 5.0).

Example Example Example Example Example Example Example ExampleComposition Composition Composition Composition Composition CompositionComposition Composition Component 1 2 3 4 5 6 7 8 Xylitol None  0.75%None  0.75% None  0.75% None  0.75% EDTA 0.015% 0.015% 0.015% 0.015%0.015% 0.015% 0.015% 0.015% MC Cellulose & Sodium  2.4%  2.4%  2.4% 2.4%  2.4%  2.4%  2.4%  2.4% Carboxymethyl Cellulose (Avicel CL611)Potassium Sorbate  0.3%  0.3%  0.3%  0.3%  0.3%  0.3%  0.3%  0.3%Propylene Glycol  1.5%  2.5%  1.5%  2.5%  1.5%  2.5%  1.5%  2.5% SodiumCitrate  1.48%  1.48%  1.48%  1.48%  1.48%  1.48%  1.48%  1.48% CitricAcid, Anhydrous  0.96%  0.96%  0.96%  0.96%  0.96%  0.96%  0.96%  0.96%Polysorbate 80 0.025% 0.025% 0.025% 0.025% 0.025% 0.025% 0.025% 0.025%N-(4-{4-[(6-butyl-8- 0.025-0.9% 0.025-0.9% 0.025-0.9% 0.025-0.9%0.025-0.9% 0.025-0.9% 0.025-0.9% 0.025-0.9% quinolinyl)oxy]-1-piperidinyl}butyl)ethane sulfonamide, as free base* Fluticasone furoateNone None  0.05%  0.05%  0.05%  0.05% None None (micronised unsolvated,polymorphic Form 1) Purified Water to 100% to 100% to 100% to 100% to100% to 100% to 100% to 100%

In Example Compositions 1 to 8, the concentation of micronisedN-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamideis given as the free base, which concentrations are 0.025% (w/w), 0.05%(w/w), 0.1% (w/w), 0.25% (w/w), 0.5% (w/w) and 0.9% (w/w), based on thetotal weight of the composition.

It will be appreciated thatN-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamidemay be used in the form of a pharmaceutically acceptable salt at anappropriate concentration, depending on the salt chosen, such as toprovide the desired concentration of free base.

Example compositions may be filled into suitable containers depending onthe chosen route of administration. For intransal administration,suitable containers are described hereinabove and typically are made ofplastics and dispense 50 to 100 μL of composition per actuation.

1. A compound of formula (I)

wherein R¹ represents straight chain C₁₋₆alkyl; a represents 1 or 2; R²represents —C₁₋₆alkylene-R³-R⁴, in which the alkylene is straight chainand is optionally substituted by one C₁₋₃alkyl group, or R² represents a5 to 7 membered ring containing one SO₂ group; R³ represents —SO₂—,—NR⁵SO₂—, —SO₂NR⁶— or —NR⁷C(O)NR⁸—; R⁴ represents —C₁₋₆alkyl,—C₅₋₇cycloalkyl optionally substituted by one or two C₁₋₃alkyl groups,—C₁₋₃alkyleneC₅₋₇cycloalkyl in which the C₅₋₇cycloalkyl is optionallysubstituted by one or two C₁₋₃alkyl groups, -aryl optionally substitutedby one or two halogen, C₁₋₃alkyl, trifluoromethyl, or cyano groups, or—C₁₋₃alkylene-aryl optionally substituted by one or two halogen,C₁₋₃alkyl, trifluoromethyl, or cyano groups; R⁵, R⁶, R⁷ and R⁸ eachindependently represent hydrogen or C₁₋₆alkyl; or together R⁶ and R⁴represent a saturated 5 to 7 membered ring, optionally containing one—O—, —S—, —NH—, or —N(CH₃)— group; or together R⁸ and R⁴ represent asaturated 5 to 7 membered ring, optionally containing one —O—, —S—,—NH—, or —N(CH₃)— group; or a salt thereof.
 2. A compound according toclaim 1 in which R¹ represents C₂₋₅alkyl; a represents 1 or 2; R²represents —C₂₋₅alkylene-R³-R⁴, in which the alkylene is straight chainand is optionally substituted by one C₁₋₃alkyl group, or R² represents a5 membered ring containing one SO₂ group; R³ represents —SO₂—, —NR⁵SO₂—,—SO₂NR⁶— or —NR⁷C(O)NR⁸—; R⁴ represents —C₁₋₄alkyl, —C₅₋₆cycloalkyl,—C₁alkyleneC₅₋₆cycloalkyl, -aryl optionally substituted by one or twohalogen, C₁₋₃alkyl, trifluoromethyl, or cyano groups, or—C₁alkylene-aryl optionally substituted by one or two halogen,C₁₋₃alkyl, trifluoromethyl, or cyano groups; R⁵, R⁶, R⁷ and R⁸ eachindependently represent hydrogen or C₁₋₃alkyl; or a salt thereof.
 3. Acompound according to claim 1 in which R¹ represents n-butyl orn-pentyl.
 4. A compound according to claim 1 in which a represents
 2. 5.A compound according to claim 1 in which R³ represents —SO₂—, —NR⁵SO₂—or —SO₂NR⁶—.
 6. A compound according to claim 1 in which R³ represents—NR⁵SO₂— or —SO₂NR⁶—.
 7. A compound according to claim 1 in which R⁴represents —C₁₋₄alkyl, —C₅₋₆cycloalkyl, —C₁alkyleneC₅₋₆cycloalkyl, -aryloptionally substituted by one or two halogen, C₁₋₃alkyl,trifluoromethyl, or cyano groups, or —C₁alkylene-aryl optionallysubstituted by one or two halogen, C₁₋₃alkyl, trifluoromethyl, or cyanogroups.
 8. A compound according to claim 1 in which R⁵, R⁶, R⁷ and R⁸each independently represent hydrogen or C₁₋₃alkyl.
 9. A compound whichis: 6-Butyl-8-({1-[2-(ethylsulfonyl)ethyl]-4-piperidinyl}oxy)quinoline;6-Butyl-8-[(1-{2-[(1,1-dimethylethyl)sulfonyl]ethyl}-4-piperidinyl)oxy]quinoline;6-Butyl-8-({1-[3-(methylsulfonyl)propyl]-4-piperidinyl}oxy)quinoline;6-Butyl-8-({1-[3-(ethylsulfonyl)propyl]-4-piperidinyl}oxy)quinoline;6-Butyl-8-({1-[3-(propylsulfonyl)propyl]-4-piperidinyl}oxy)quinoline;6-Butyl-8-[(1-{3-[(1-methylethyl)sulfonyl]propyl}-4-piperidinyl)oxy]quinoline;6-Butyl-8-[(1-{3-[(1,1-dimethylethyl)sulfonyl]propyl}-4-piperidinyl)oxy]quinoline;6-Butyl-8-({1-[3-(cyclopentylsulfonyl)propyl]-4-piperidinyl}oxy)quinoline;6-Butyl-8-[(1-{4-[(1,1-dimethylethyl)sulfonyl]butyl}-4-piperidinyl)oxy]quinoline;6-Butyl-8-({1-[3-(ethylsulfonyl)butyl]-4-piperidinyl}oxy)quinoline;8-({1-[3-(Ethylsulfonyl)propyl]-4-piperidinyl}oxy)-6-pentylquinoline;6-Butyl-8-[((3R)-1-{3-[(1,1-dimethylethyl)sulfonyl]propyl}-3-pyrrolidinyl)oxy]quinoline;6-Butyl-8-{[1-(1,1-dioxidotetrahydro-3-thienyl)-4-piperidinyl]oxy}quinoline;N-(2-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}ethyl)ethanesulfonamide;N-(2-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}ethyl)-2-methyl-1-propanesulfonamide;N-(2-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}ethyl)benzenesulfonamide;N-(3-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)ethanesulfonamide;N-(3-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)-1-propanesulfonamide;N-(3-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)-2-propanesulfonamide;N-(3-{4-[(6-Pentyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)ethanesulfonamide;N-(3-{4-[(6-Pentyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)-1-propanesulfonamide;N-(4-{-4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)methanesulfonamide;N-(4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide;N-(4-{-4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)-1-propanesulfonamide;N-(4-{-4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)-2-propanesulfonamide;N-(4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)-2-methyl-1-propanesulfonamide;N-(4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)cyclohexanesulfonamide;N-(4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)-1-cyclohexylmethanesulfonamide;N-(4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)-N-methylethanesulfonamide;N-(4-{4-[(6-Pentyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide;N-(5-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}pentyl)methanesulfonamide;N-(5-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}pentyl)ethanesulfonamide;2-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}-N-(1,1-dimethylethyl)ethanesulfonamide;3-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}-N-(1,1-dimethylethyl)-1-propanesulfonamide;4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}-N-propyl-1-butanesulfonamide;orN-(3-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)-N-propylurea;or a pharmaceutically acceptable salt thereof.
 10. A compound accordingto claim 1 which isN-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide,or a pharmaceutically acceptable salt thereof. 11-18. (canceled)
 19. Acomposition which comprises a compound of formula (I)

wherein R¹ represents straight chain C₁₋₆alkyl; a represents 1 or 2; R²represents —C₁₋₆alkylene-R³-R⁴, in which the alkylene is straight chainand is optionally substituted by one C₁₋₃alkyl group, or R² represents a5 to 7 membered ring containing one SO₂ group; R³ represents —SO₂—,—NR⁵SO₂—, —SO₂NR⁶— or —NR⁷C(O)NR⁸—; R⁴ represents —C₁₋₆alkyl,—C₅₋₇cycloalkyl optionally substituted by one or two C₁₋₃alkyl groups,—C₁₋₃alkyleneC₅₋₇cycloalkyl in which the C₅₋₇cycloalkyl is optionallysubstituted by one or two C₁₋₃alkyl groups, -aryl optionally substitutedby one or two halogen, C₁₋₃alkyl, trifluoromethyl, or cyano groups, or—C₁₋₃alkylene-aryl optionally substituted by one or two halogen,C₁₋₃alkyl, trifluoromethyl, or cyano groups; R⁵, R⁶, R⁷ and R⁸ eachindependently represent hydrogen or C₁₋₆alkyl; or together R⁶ and R⁴represent a saturated 5 to 7 membered ring, optionally containing one—O—, —S—, —NH—, or —N(CH₃)— group; or together R⁸ and R⁴ represent asaturated 5 to 7 membered ring, optionally containing one —O—, —S—,—NH—, or —N(CH₃)— group; pharmaceutically acceptable salt thereof, andone or more pharmaceutically acceptable carriers and/or excipients.20-31. (canceled)
 32. A method for the treatment of inflammatory and/orallergic diseases of the respiratory tract which comprises administeringto a patient in need thereof an effective amount of a compound offormula (I)

wherein R¹ represents straight chain C₁₋₆alkyl; a represents 1 or 2; R²represents —C₁₋₆alkylene-R³-R⁴, in which the alkylene is straight chainand is optionally substituted by one C₁₋₃alkyl group, or R² represents a5 to 7 membered ring containing one SO₂ group; R³ represents —SO₂——NR⁵SO₂— —SO₂NR⁶— or —NR⁷C(O)NR⁸—; R⁴ represents —C₁₋₆alkyl,—C₅₋₇cycloalkyl optionally substituted by one or two C₁₋₃alkyl groups,—C₁₋₃alkyleneC₅₋₇cycloalkyl in which the C₅₋₇cycloalkyl is optionallysubstituted by one or two C₁₋₃alkyl groups, -aryl optionally substitutedby one or two halogen, C₁₋₃alkyl, trifluoromethyl, or cyano groups, or—C₁₋₃alkylene-aryl optionally substituted by one or two halogen,C₁₋₃alkyl, trifluoromethyl, or cyano groups; R⁵, R⁶, R⁷ and R⁸ eachindependently represent hydrogen or C₁₋₆alkyl; or together R⁶ and R⁴represent a saturated 5 to 7 membered ring, optionally containing one—O—, —S—, —NH—, or —N(CH₃)— group; or together R⁸ and R⁴ represent asaturated 5 to 7 membered ring, optionally containing one —O—, —S—,—NH—, or —N(CH₃)— group, or a pharmaceutically acceptable salt thereof33-34. (canceled)
 35. A method according to claim 32 in which thedisease is allergic rhinitis.
 36. A composition according to claim 19which comprises a compound which is:6-Butyl-8-({1-[2-(ethylsulfonyl)ethyl]-4-piperidinyl}oxy)quinoline;6-Butyl-8-[(1-{2-[(1,1-dimethylethyl)sulfonyl]ethyl}-4-piperidinyl)oxy]quinoline;6-Butyl-8-({1-[3-(methylsulfonyl)propyl]-4-piperidinyl}oxy)quinoline;6-Butyl-8-({1-[3-(ethylsulfonyl)propyl]-4-piperidinyl}oxy)quinoline;6-Butyl-8-({1-[3-(propylsulfonyl)propyl]-4-piperidinyl}oxy)quinoline;6-Butyl-8-[(1-{3-[(1-methylethyl)sulfonyl]propyl}-4-piperidinyl)oxy]quinoline;6-Butyl-8-[(1-{3-[(1,1-dimethylethyl)sulfonyl]propyl}-4-piperidinyl)oxy]quinoline;6-Butyl-8-({1-[3-(cyclopentylsulfonyl)propyl]-4-piperidinyl}oxy)quinoline;6-Butyl-8-[(1-{4-[(1,1-dimethylethyl)sulfonyl]butyl}-4-piperidinyl)oxy]quinoline;6-Butyl-8-({1-[3-(ethylsulfonyl)butyl]-4-piperidinyl}oxy)quinoline;8-({1-[3-(Ethylsulfonyl)propyl]-4-piperidinyl}oxy)-6-pentylquinoline;6-Butyl-8-[((3R)-1-{3-[(1,1-dimethylethyl)sulfonyl]propyl}-3-pyrrolidinyl)oxy]quinoline;6-Butyl-8-{[1-(1,1-dioxidotetrahydro-3-thienyl)-4-piperidinyl]oxy}quinoline;N-(2-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}ethyl)ethanesulfonamide;N-(2-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}ethyl)-2-methyl-1-propanesulfonamide;N-(2-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}ethyl)benzenesulfonamide;N-(3-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)ethanesulfonamide;N-(3-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)-1-propanesulfonamide;N-(3-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)-2-propanesulfonamide;N-(3-{4-[(6-Pentyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)ethanesulfonamide;N-(3-{4-[(6-Pentyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)-1-propanesulfonamide;N-(4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)methanesulfonamide;N-(4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide;N-(4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)-1-propanesulfonamide;N-(4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)-2-propanesulfonamide;N-(4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)-2-methyl-1-propanesulfonamide;N-(4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)cyclohexanesulfonamide;N-(4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)-1-cyclohexylmethanesulfonamide;N-(4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)-N-methylethanesulfonamide;N-(4-{4-[(6-Pentyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide;N-(5-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}pentyl)methanesulfonamide;N-(5-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}pentyl)ethanesulfonamide;2-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}-N-(1,1-dimethylethyl)ethanesulfonamide;3-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}-N-(1,1-dimethylethyl)-1-propanesulfonamide;4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}-N-propyl-1-butanesulfonamide;orN-(3-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)-N-propylurea;or a pharmaceutically acceptable salt thereof.
 37. A compositionaccording to claim 19 which comprises a compound which isN-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide,or a pharmaceutically acceptable salt thereof.
 38. A method according toclaim 32 in which the compound is selected from:6-Butyl-8-({1-[2-(ethylsulfonyl)ethyl]-4-piperidinyl}oxy)quinoline;6-Butyl-8-[(1-{2-[(1,1-dimethylethyl)sulfonyl]ethyl}-4-piperidinyl)oxy]quinoline;6-Butyl-8-({1-[3-(methylsulfonyl)propyl]-4-piperidinyl}oxy)quinoline;6-Butyl-8-({1-[3-(ethylsulfonyl)propyl]-4-piperidinyl}oxy)quinoline;6-Butyl-8-({1-[3-(propylsulfonyl)propyl]-4-piperidinyl}oxy)quinoline;6-Butyl-8-[(1-{3-[(1-methylethyl)sulfonyl]propyl}-4-piperidinyl)oxy]quinoline;6-Butyl-8-[(1-{3-[(1,1-dimethylethyl)sulfonyl]propyl}-4-piperidinyl)oxy]quinoline;6-Butyl-8-({1-[3-(cyclopentylsulfonyl)propyl]-4-piperidinyl}oxy)quinoline;6-Butyl-8-[(1-{4-[(1,1-dimethylethyl)sulfonyl]butyl}-4-piperidinyl)oxy]quinoline;6-Butyl-8-({1-[3-(ethylsulfonyl)butyl]-4-piperidinyl}oxy)quinoline;8-({1-[3-(Ethylsulfonyl)propyl]-4-piperidinyl}oxy)-6-pentylquinoline;6-Butyl-8-[((3R)-1-{3-[(1,1-dimethylethyl)sulfonyl]propyl}-3-pyrrolidinyl)oxy]quinoline;6-Butyl-8-{[1-(1,1-dioxidotetrahydro-3-thienyl)-4-piperidinyl]oxy}quinoline;N-(2-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}ethyl)ethanesulfonamide;N-(2-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}ethyl)-2-methyl-1-propanesulfonamide;N-(2-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}ethyl)benzenesulfonamide;N-(3-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)ethanesulfonamide;N-(3-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)-1-propanesulfonamide;N-(3-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)-2-propanesulfonamide;N-(3-{4-[(6-Pentyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)ethanesulfonamide;N-(3-{4-[(6-Pentyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)-1-propanesulfonamide;N-(4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)methanesulfonamide;N-(4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide;N-(4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)-1-propanesulfonamide;N-(4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)-2-propanesulfonamide;N-(4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)-2-methyl-1-propanesulfonamide;N-(4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)cyclohexanesulfonamide;N-(4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)-1-cyclohexylmethanesulfonamide;N-(4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)-N-methylethanesulfonamide;N-(4-{4-[(6-Pentyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide;N-(5-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}pentyl)methanesulfonamide;N-(5-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}pentyl)ethanesulfonamide;2-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}-N-(1,1-dimethylethyl)ethanesulfonamide;3-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}-N-(1,1-dimethylethyl)-1-propanesulfonamide;4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}-N-propyl-1-butanesulfonamide;andN-(3-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)-N-propylurea;or a pharmaceutically acceptable salt thereof.
 39. A method according toclaim 32 in which the compound isN-(4-{-4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide,or a pharmaceutically acceptable salt thereof.